Skip Content
You are currently on the new version of our website. Access the old version .
MDPIMDPI
Search all articles
LifeLife
Download PDF
  • Review
  • Open Access

29 July 2023

Voltage-Gated Na+ Channels in Alzheimer’s Disease: Physiological Roles and Therapeutic Potential

,
,
,
,
and
Department of Pharmacology & Toxicology, The University of Texas Medical Branch, Galveston, TX 77555, USA
*
Author to whom correspondence should be addressed.
Life2023, 13(8), 1655;https://doi.org/10.3390/life13081655
This article belongs to the Special Issue Ion Channels and Neurological Disease
Version Notes
Order Reprints

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia and is classically characterized by two major histopathological abnormalities: extracellular plaques composed of amyloid beta (Aβ) and intracellular hyperphosphorylated tau. Due to the progressive nature of the disease, it is of the utmost importance to develop disease-modifying therapeutics that tackle AD pathology in its early stages. Attenuation of hippocampal hyperactivity, one of the earliest neuronal abnormalities observed in AD brains, has emerged as a promising strategy to ameliorate cognitive deficits and abate the spread of neurotoxic species. This aberrant hyperactivity has been attributed in part to the dysfunction of voltage-gated Na+ (Nav) channels, which are central mediators of neuronal excitability. Therefore, targeting Nav channels is a promising strategy for developing disease-modifying therapeutics that can correct aberrant neuronal phenotypes in early-stage AD. This review will explore the role of Nav channels in neuronal function, their connections to AD pathology, and their potential as therapeutic targets.

1. Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder classically characterized by the accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau aggregates that disrupt synaptic function, ultimately culminating in synaptic decline and neurodegeneration [1]. Current FDA-approved small-molecule therapeutics for AD include acetylcholinesterase inhibitors [2] and NMDA receptor antagonists [3], which are effective in providing symptomatic relief but lack disease-modifying properties. FDA-approved monoclonal antibodies, such as aducanumab [4] and lecanemab [5], show efficacy in the clearance of Aβ, but there is a lack of evidence that they convincingly slow AD progression among large clinical populations. Thus, there remains an unmet need for the development of disease-modifying therapeutics for AD.
Accumulation of neurotoxic proteins in key brain regions induces neuronal deficits that are widely thought to be the cause of AD symptoms. The precise mechanisms of Aβ- and tau-mediated AD pathology remain to be elucidated, an issue which is further complicated by interpatient variability [6]. Nonetheless, AD is defined by the accumulation of Aβ and tau deposits [7]. Aβ deposition begins in the frontomedial and temporobasal areas, spreading then to the remaining neocortical regions [8]. Tau accumulation is first observed in the entorhinal cortex [9] and spreads successively into the hippocampus [10]. While intricacies of the relationship between Aβ and tau seeding and accumulation remain elusive, several studies suggest that Aβ may facilitate the seeding of tau [11,12,13,14].
The Aβ and tau proteins progressively accumulate at synapses, interrupting synaptic communication through the degeneration of dendritic spines [15], leading to axonal degeneration and eventual neuronal loss [16]. These phenomena progressively hinder the function of the hippocampal circuit, inducing deficits in long-term potentiation (LTP) and long-term depression (LTD), two forms of synaptic plasticity widely thought to be the basis of progressive memory loss in AD [17].

2. Hippocampal Hyperactivity in Early-Stage AD

Prior to global neurodegeneration and resultant progressive loss of memory associated with late stages of AD, hippocampal hyperactivity is observed in rodent models [18,19,20] as well as human patients [21,22,23,24]. Functional MRI studies indicate that patients with mild cognitive impairment (MCI) display increased hippocampal activation during memory-related tasks compared to healthy adults [25,26], and this phenomenon has emerged as a potential biomarker of mild cognitive impairment and early-stage AD [27,28].
This hyperactivity occurs prior to amyloid plaque deposition [20,29,30], positioning the phenotype as one of the first neurophysiological alterations in the AD brain. While there remain many questions to be answered regarding the precise mechanisms, origins, and consequences of this phenotype, it has emerged as a common feature in AD that precedes greater cognitive decline [31]. In support of this aberrant elevated neuronal activity as a precursor to AD, it has been has been linked to cognitive dysfunction and decreased memory performance [27,31,32] as well as the production and accumulation of Aβ and tau [27,33,34,35,36,37,38]. Moreover, amelioration of hippocampal hyperactivity using anti-epileptics, such as levetiracetam, has been shown to improve cognition and memory performance in rodent models and patients with MCI or early-stage AD [32,39,40]. Therefore, given its acute and longitudinal impacts on AD pathophysiology, correcting hippocampal hyperactivity represents a promising and potentially disease-modifying approach for AD treatment.
As described above, the hyperactivity phenotype is linked to various neuronal processes that accelerate the rate of AD progression. Therefore, evaluation of molecular contributors to the phenotype is warranted. On account of their centrality in initiating and propagating the action potential (AP) [41,42], in this review, we discuss the contribution of voltage-gated sodium (Nav) channels to the hyperactivity phenotype observed in early-stage AD, their function as the disease progresses, and their viability as therapeutic targets for the disease.

3. Overview of Nav Channels in AD Pathology

Broadly speaking, proper hippocampal function is mediated by the activity of glutamatergic principal neurons and GABAergic interneurons [43,44,45]. Thus, in order to ameliorate aberrant hyperactivity, the functional contributions of each neuronal subtype must be considered. Glutamatergic principal cells comprise the vast majority of hippocampal neurons and are densely packed into layers [46], notably the dentate gyrus (DG), CA3, and CA1 regions whose excitatory connections compose the trisynaptic circuit [47,48]. GABAergic inhibitory interneurons, despite only comprising ~10% of hippocampal cells [43,46], dramatically influence the activity of the hippocampal circuit [49]. Unlike principal cells, interneuron subtypes display significant intrinsic and morphological diversity and are disseminated throughout all hippocampal subfields [43]. The diversity of interneuron axonal projections lends them the capacity to synapse onto single cells or neuronal clusters throughout the hippocampal formation, providing essential GABAergic tone [49,50] and preventing excessive excitation of principal neurons through feedforward and feedback inhibition [43,50]. Hippocampal network dynamics rely on the balance between the excitatory and inhibitory signals (E/I balance) [51,52] produced by the aforementioned cell types. Therefore, pathological deviations in hippocampal activity can be ascribed to altered excitability of either principal cells or interneurons.
Nav channels, which are molecular determinants of neuronal excitability, consist of nine distinct isoforms (Nav1.1–Nav1.9) [53] that have varying expression profiles among different cell types [54,55,56]. Nav1.1 and Nav1.6 are of particular interest as they display distinctive enriched expression in hippocampal interneurons [57,58] and principal neurons [54,59], respectively, enabling the initiation and propagation of action potentials in these cell types. In early-stage AD, Nav1.1 and Nav1.6 display unique expression profiles and functional activity [29,60], contributing centrally to the aberrant excitability of interneurons and principal cells and resulting in hippocampal hyperactivity. Given the dichotomous functional roles of Nav1.1 and Nav1.6 channels in modulating hippocampal activity, the two isoforms will be considered separately. In this section, the physiological roles and disease-associated functions of Nav1.1 and Nav1.6 channels in their respective cell types will be discussed.

3.1. Nav1.1

GABAergic inhibitory interneurons comprise a small percentage of hippocampal neurons [46] but are able to contribute substantially to the regulation of hippocampal excitability due to their distribution and diverse axonal projections [43,44]. Hippocampal interneurons are classified into several major subtypes based on neuronal molecular expression, including somatostatin neurons, parvalbumin neurons, neuropeptide Y neurons, vasoactive intestinal peptide neurons, and cholecystokinin neurons [61]. Of these subtypes, somatostatin (SOM)- and parvalbumin (PV)-positive interneurons comprise a large majority (~70–80%) of the hippocampal interneuron population [62]. The Nav1.1 channel is predominantly expressed in inhibitory interneurons [60,63], where it serves as a key molecular determinant of intrinsic firing. With its subcellular localization in soma, axon initial segments (AIS), and axons, Nav1.1 channels facilitate the initiation and propagation of action potentials in these cells [63,64].
Loss-of-function mutations to Nav1.1 result in reduced Na+ current, causing reduced action potential firing in interneurons [57]. The imbalance caused by decreased interneuron activity can lead to seizures and is the leading cause of multiple epilepsies and other disorders, most notably Dravet’s syndrome [58,65]. It has been shown that epileptiform activity, particularly in the form of nonconvulsive seizures, is common in early-stage AD patients [66]. Multiple lines of evidence indicate that this epileptiform activity accelerates the rate of AD pathology and worsening of cognitive symptoms [66,67]. Along with displaying epileptiform activity, decreased levels of Nav1.1 expression have been observed across multiple transgenic AD mouse models [68,69,70] as well as AD patients [70], further supporting the pathophysiological role of this channel in AD. Early studies demonstrated that GABAergic interneurons are resistant to Aβ and tau protein deposition [71,72]. Highlighting this finding, in a study of the expression of hyperphosphorylated tau in AD patients, Blazquez-Llorca et al. found that of almost 4000 PV-positive interneurons in the hippocampal formation and entorhinal cortex analyzed, paired-helical filaments of tau were present in only two [73]. Despite GABAergic interneurons being resistant to Aβ and tau deposition [71,72], the activity of these neurons is dysfunctional in AD, and the precise pathophysiological mechanisms are the focus of many recent investigations [74,75,76,77].
One proposed mechanism by which GABAergic interneuron activity becomes compromised in AD is through the activity of β-site APP cleaving enzyme 1 (BACE1) [78], a secretase involved in Aβ production. Crucially, BACE1 activity and levels are significantly increased in the brains of AD patients, which is thought to contribute to the progression of AD by increasing Aβ [79,80,81]. In addition to its role in Aβ production, the Nav channel β2 subunit, which is covalently linked to the Nav1.1 alpha subunit, is a substrate for BACE1 [78]. Moreover, increased BACE1 causes a reduction in Nav1.1 cell surface expression [78], which would be expected to decrease the excitability of GABAergic interneurons. Consistent with such an expectation, PV interneurons in the hippocampus display reduced excitability in rodent models of AD [82]. Therefore, despite their apparent resistance to Aβ and tau pathology [71,72,73], depletion of Nav1.1 and suppression of its activity in hippocampal interneurons is potentially a major contributor to network dysfunction and cognitive deficits in AD [70].

3.2. Nav1.6

Contrarily to GABAergic interneurons, glutamatergic principal cells comprise a majority of neurons in the hippocampus [46]. Also, in contrast to interneurons, principal cells display a distinct layered organizational pattern with a relatively high level of anatomical uniformity [83,84]. Nav1.6 is extensively expressed in the adult human brain and is the predominant Nav isoform in hippocampal principal cells [85]. Nav1.6 displays a distinctive pattern of subcellular localization, with concentrated expression at the AIS and nodes of Ranvier in hippocampal principal neurons [59]. This pattern allows the channel to centrally regulate action potential initiation, propagation, and saltatory conduction in these cells [86] and govern the spike threshold of glutamatergic principal cells and contribute to synaptic integration [54]. This distinct role of Nav1.6 is due to its accumulation in the distal AIS and hyperpolarized voltage dependence of activation, setting it apart from other Nav channel isoforms at the AIS. Given the central role of Nav1.6 in regulating the action potential in excitatory neurons, both gain-of-function and loss-of-function mutations have been found to have pathogenic consequences [59]. Functional alterations to the Nav1.6 channel have been implicated in a number of neuropsychiatric disorders [59,87,88,89]. It has been observed that haploinsufficiency of the SCN8A gene results in cognitive impairment and has been linked to intellectual disability [90]. Conversely, gain-of-function mutations to Nav1.6, which promote aberrant high-frequency neuronal firing, are closely linked with epileptiform activity [88,91].
In the context of AD, Nav1.6 has emerged as the focus of many investigations regarding network abnormalities and disease progression [29,34,92,93]. It has been observed that acute exposure to soluble Aβ oligomers results in hyperactivity of CA1 pyramidal neurons [94]. Further, it was observed that soluble Aβ exposure selectively upregulated the expression and function of Nav1.6 [29] and that pyramidal cell hyperactivity was abolished following treatment with Nav channel blockers [94], implicating this Nav channel isoform as a driver of AD-related hyperactivity. Additionally, it is observed that amyloid precursor protein (APP) both directly interacts with Nav1.6 [93] and enhances Nav1.6 surface expression via a G protein-coupled JNK pathway [92]. Functionally, this results in the potentiation of Nav1.6-mediated Na+ currents [92]. These mechanisms provide convincing evidence for the contribution of Nav1.6 to the hyperexcitation of principal neurons in early AD and reveal novel, potentially synergistic pathways that drive AD pathology.

4. Therapeutic Potential of Nav Channels for AD

Nav1.1 and Nav1.6 channels have distinct roles in hippocampal hyperactivity and are potential therapeutic targets for early-stage AD [39,69]. However, current Nav channel modulators have the potential for off-target effects due to a lack of isoform selectivity. With the development of high-resolution Nav channel structures [72] and a better understanding of the biology of isoform-specific accessory proteins and signaling pathways [95], progress has been made towards developing targeted therapies that are selective for specific isoforms. This section will discuss Nav1.1 and Nav1.6 modulation mechanisms and potential therapeutic strategies for early AD.

4.1. Nav1.1 Activation

Increased BACE1 activity in early-stage AD reduces Nav1.1 cell surface expression, leading to decreased excitability of GABAergic interneurons in the hippocampus and contributing to increased excitatory/inhibitory tone. Restoring proper interneuron activity may help correct this imbalance. One potential therapeutic strategy for overcoming deficits in interneuron activity in the hippocampus is the transplantation of interneuron progenitor cells [96]. This involves the extraction of progenitor cells from the medial ganglionic eminence and transplantation into the brain of the affected individual [96]. Following the procedure, these cells integrate into the existing neuronal circuitry and mature into functional inhibitory interneurons. In AD rodent models, it has been observed that hippocampal transplantation of wild-type progenitor cells provides little to no improvement; however, transplantation of progenitor cells overexpressing the Nav1.1 channel results in improved behavior and cognitive performance [60]. Conversely, transplantation of Nav1.1-deficient progenitor cells impaired learning and behavioral functions [60]. Despite encouraging results following the transplantation of Nav1.1 interneuron progenitor cells in rodent models, the associated risks may hinder the translatability of this approach. Gene therapy represents an alternative strategy for the restoration of Nav1.1 activity and interneuron activity [97,98]. The feasibility of this approach has been demonstrated in rodent models, where voltage-gated potassium channels were delivered for the treatment of epilepsy or neuropathic pain [99,100]. Recent and promising developments involving engineered prokaryotic Nav channels for cardiac arrhythmias also illustrate the potential of this concept for clinical applications [101] and may inform future investigations regarding the delivery of neuronal Nav channels.
Cumulatively, these studies not only further indicate the importance of interneuron function during early AD but also establish that interneuron-based interventions for hippocampal hyperactivity are reliant on Nav1.1. Thus, pharmacologically potentiating Nav1.1 activity represents a promising therapeutic avenue for early-stage AD. There are several known classes of sodium channel activators, such as toxins from the venom of several organisms [102] or pyrethroid insecticides [103]. While therapeutic development from these agents is challenging due to their overall toxic effects, using these chemicals to selectively activate Nav channels allows for the demonstration of therapeutic benefit. For example, δ-theraphotoxin-Hm1a and δ-theraphotoxin-Hm1b (Hm1a and Hm1b) are toxins derived from the venom of the Heteroscodra maculata tarantula that potentiates the activity of the Nav1.1 channel selectively [104,105]. Hm1a-mediated activation of Nav1.1 is able to restore the function of inhibitory interneurons from Dravet syndrome mice without affecting the activity of excitatory neurons, and intracerebroventricular infusion of Hm1a in the Dravet syndrome rodent model rescued the animals from seizures and premature death [105]. While Hm1a and Hm1b exhibit high structural homology, further investigation revealed that Hm1b is more stable in biological fluids [106]. Electrophysiological studies revealed that the Hm1b peptide causes a hyperpolarizing shift in the voltage dependence of activation and delays fast inactivation of the Nav1.1 channel, increasing both peak and sustained Nav1.1 currents [106] through stabilizing interactions with its domain four voltage sensor [106]. While further optimization is required for clinical applications, these toxins demonstrate the value of Nav1.1 activation for restoring inhibitory interneuron activity in hyperexcitability disorders.
Given the considerable potential of Nav1.1 activators for Dravet syndrome and other excitability disorders, the development of small molecule Nav1.1 agonists has emerged as a rich area of investigation [102,107,108]. A 2019 high-throughput screening campaign conducted by Takeda Pharmaceutical Company led to the identification of a series of 4-phenyl-2-(pyrrolidinyl)-nicotinamide derivatives as potent and selective Nav1.1 activators [108], and structural optimization yielded a compound with favorable druglike properties that achieves brain concentrations comparable to its potency in vitro. While further investigations are required to determine the safety and translational of this compound’s effects, it holds potential as a therapeutic for epilepsy disorders and thus may be applied for hyperexcitability in early-stage AD.

4.2. Nav1.6 Inhibition

In contrast to Nav1.1, Nav1.6 is primarily expressed in excitatory neurons, and increased expression and activity of the channel are observed in AD brains as a result of Aβ oligomer exposure [29,92]. Knockdown of the Nav1.6 channel in AD rodents rescues LTP deficits and mitigates hippocampal hyperactivity in AD models, restoring memory-associated beta, gamma, delta, and theta waves to normal levels [34]. Additionally, knocking down Nav1.6 decreased both the number and size of Aβ plaques in these animals, providing evidence for the disease-modifying potential of Nav1.6 modulation [34]. The reduction in Aβ plaque accumulation is caused by reduced transcription of BACE1. When Aβ oligomers are present, genetic knockdown or pharmacological inhibition of Nav1.6 reduces BACE1 transcription and BACE1-mediated cleavage of APP, resulting in decreased Aβ production and plaque accumulation [34]. Intriguingly, while treatment with levetiracetam, an anti-epileptic with a mechanism independent of Nav channels, improves memory and cognitive performance, it fails to alter Aβ production or plaque accumulation [109]. Therefore, reducing hippocampal hyperactivity, specifically through modulation of Nav1.6, could provide both acute improvements to memory and cognition as well as simultaneously reducing AD pathophysiology.
NBI-921352 is a Nav channel inhibitor being investigated for the treatment of epilepsy caused by Nav1.6 gain-of-function mutations. It displays high selectivity for Nav1.6~130-fold greater potency for Nav1.6 over Nav1.1 and Nav1.2 isoforms [110]. By stabilizing Nav1.6 inactivated state, NBI-921352 inhibits persistent and resurgent currents, which are the source of hyperexcitability in pyramidal neurons [91]. Crucially, while NBI-921352 reduces excitability in principal cells, the activity of fast-spiking interneurons is spared [110]. Nav1.6 inhibition has shown promise in pre-clinical models of AD by correcting synaptic dysfunction, reducing Aβ plaque accumulation, and improving cognitive function [34]. Phase 1 trials indicate that NCI-921352 is well-tolerated in healthy adults and displays evidence of CNS activity [111]. Further studies are needed to assess NBI-921352’s efficacy in diseased individuals. However, increased expression and activity of Nav1.6 in early AD provides the opportunity for increased potency in diseased tissues, and functional studies illustrate the potential of Nav1.6 as a therapeutic target for the correction of aberrant hyperexcitability.

5. Alternative Strategies for Modulation of Nav Channels

While the pore-forming α-subunit of Nav channels is primarily responsible for their physiological functions and has been the target for drug development of current Nav channel inhibitors, these channels rely on an array of intracellular channel-associated proteins (ChAPs) and post-translational modifications (PTMs) via various kinases for full function [112,113] (Figure 1, Table 1). These ChAPs have divergent regulatory effects and provide both isoforms as well as tissue specificity due to their unique intermolecular interactions with the channel as well their differential expression profiles in tissues [95,114,115,116]. In addition to selectivity, modulation of the Nav channel via ChAP complexes allows for bidirectional regulation of channel activity by either facilitating or inhibiting complex formation [115,117,118], therefore offering the potential for precise tuning of Nav channel activity through mechanisms beyond traditional agonism and inhibition. Promising ChAP modulators targeting specific regions, such as the C-terminal domain [113,114,119] of Nav channels, have been identified. These ChAP modulators hold the potential to pharmacologically modulate Nav channels with better precision and specificity. Additionally, many kinases have been intimately linked with intracellular ChAPs and exhibit altered functions or expression patterns in AD. Thus, targeting the functional interactions between the Nav channels, their interactors, and disease-associated kinase signaling pathways represents another novel strategy for AD drug development.
Figure 1. Schematic representation of Nav channel α- and β- subunit structure.
Table 1. Summary of Nav1.1 and Nav1.6 post-translational modifications (PTMs) and regulatory interactions with AD-associated proteins.

5.1. Modulation of Nav Channels via Kinase Signaling Pathways

In the AD brain, several kinase pathways are dysregulated, and the resultant alterations in signaling via these pathways are thought to contribute directly to AD progression [89,90,91]. Intriguingly, many of the kinases and associated signaling proteins linked with AD pathology are regulators of Nav1.1 or Nav1.6 and exert their functional effects via post-translational modifications (PTMs) and/or direct binding to the channel (Table 1) [92]. Thus, targeting the functional interactions between Nav1.1 or 1.6 and disease-associated proteins represents a novel strategy for AD drug development—and could allow for improved tissue selectivity over agents that modulate Nav channels alone. This section will explore several proteins with pathological links to AD, their regulatory effects on Nav channels, and how their interactions may be modulated to ameliorate hippocampal hyperactivity.

5.1.1. Ca2+/Calmodulin-Dependent Protein Kinase

Calcium dysregulation during AD has long been investigated for its role in facilitating various facets of synaptic dysfunction and AD neuropathology [124,125,126,127]. Critically, aberrant alterations in Ca2+ signaling are detected in AD rodent models prior to severe memory impairments or histopathological biomarkers [124,128], indicating that correcting aberrant Ca2+ signaling and its downstream consequences may have disease-modifying potential. Increased Ca2+ levels in AD neurons occur through entry from extracellular space via Ca2+ permeable channels such as NMDA receptors [129] and voltage-gated calcium channels [130] or release from intracellular Ca2+ stores. These fluctuations in intracellular calcium are processed through the binding of Ca2+ ions to proteins such as calmodulin (CaM) [131]. The Ca2+/CaM-dependent protein kinases (CaMKs) are the primary binding partners of Ca2+/CaM complexes and are thus major effectors of alterations to Ca2+ ion flux in AD [132]. CaMKII, a member of the CaMK family, is a serine-threonine kinase that has altered expression and activity in the AD brain [133]. Following activation by Ca2+/CaM, CaMKII temporarily retains its kinase activity through autophosphorylation of its Thr286 residue [134]. The coupling of CaMKII with Nav channels has been shown to modulate excitability through the regulation of sodium currents across multiple Nav isoforms and cell types [135,136]. Notably, recent reports indicate that CaMKII phosphorylates Nav1.6, enhancing channel activity and Nav1.6-mediated neuronal excitability [121]. Moreover, inhibition of CaMKII is observed to ameliorate the pathological consequences of Nav1.6 gain-of-function mutations, which result in hyperexcitability disorders [137]. Therefore, inhibiting CaMKII-mediated phosphorylation of the Nav1.6 channel in early AD may represent a novel strategy to ameliorate hippocampal hyperactivity.

5.1.2. Mitogen-Activated Protein Kinase

Mitogen-activated protein kinases (MAPKs) are a family of protein kinases best known for their contribution to various diverse cellular processes, including proliferation, inflammation, and apoptosis [138,139]. The MAPK family is comprised of 3 classes in mammals, extracellular-signal-regulated kinases (ERKS), Jun-amino-terminal kinases (JNKs), and stress-activated protein kinases (p38) [140]. The p38 MAPKs consist of 4 distinct isoforms: p38α, p38β, p38γ, and p38δ. Of particular interest, p38α is highly expressed in the cortex and hippocampus [141] and has been implicated as a regulator of synaptic plasticity [141,142]. In AD, elevated activity of p38 MAPKs is observed in the hippocampus during early phases [143,144], where they contribute to excitotoxicity and tau phosphorylation [145]. However, isoform-selective functional studies have revealed that the p38α isoform is likely the primary driver of AD pathogenesis [146], while other isoforms serve lesser pathogenic roles or potentially exert neuroprotective effects [147]. Nonetheless, given the consensus that p38α is a driver of AD pathology, inhibitors of this isoform have been evaluated and show some promise in ameliorating tau hyperphosphorylation, synaptic decline, AD-associated neuroinflammation, and cognitive impairment [148,149]. p38α has been identified as a direct regulator of Nav1.6 through phosphorylation of a Pro-Gly-Ser553-Pro motif intracellular loop L1, which results in reduced Nav1.6-mediated currents [150]. However, this effect is dependent upon the Pro-Gly-Tyr1945 motif of the Nav1.6 C-terminal tail, which is responsible for the binding of Nedd4-2 ubiquitin ligase and subsequent internalization of the channel [122]. Curiously, however, in the absence of a functional Pro-Gly-Try1945 motif, it is observed that p38 phosphorylation of Nav 1.6 enhances peak current density [122], indicating that p38 phosphorylation of Nav1.6 may have opposing effects on Nav1.6-mediated neuronal excitability dependent on the function of Nedd4-2. Haploinsufficiency of Nedd4-2 is linked to increased seizure susceptibility [151], which is a hallmark symptom of prodromal AD [30,66,67]. Thus, it is possible that dysfunctional Nedd4-2 reduces Nav1.6 internalization and allows functional upregulation of the channel via p38α, ultimately resulting in aberrant hyperexcitability. The precise functional alterations to p38α and Nedd4-2 and their resultant effects with Nav1.6 during early-stage AD remain to be fully elucidated. Nonetheless, the powerful modulation of Nav1.6 induced by p38α through S553 phosphorylation warrants further investigation, and modulation of this system may allow for the regulation of hippocampal activity in early AD.

5.1.3. PI3K/AKT/GSK3β

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway contributes to a broad range of physiological processes in the brain, including cell proliferation, differentiation, autophagy, and intraneuronal trafficking [152,153,154]. PI3K is the most upstream effector of this signaling cascade and is canonically activated by receptor tyrosine kinases in response to extracellular stimuli, followed by recruitment of its catalytic p110 subunit, which enables PI3K-medicated AKT phosphorylation [154,155]. Activated AKT then exerts modulatory effects on a myriad of downstream signaling molecules via phosphorylation and complexation, including mTOR, GABA receptors, and eukaryotic translation initiation factor α (eIF2α) [156,157], which mechanistically link the PI3K/AKT signaling axis to the regulation of synaptic plasticity. In AD brains, dysfunctional PI3K/AKT signaling has been linked to various pathogenic processes [153], including Aβ and tau pathology [158], neuroinflammation, impaired glucose metabolism, and oxidative stress [159], and restoration of its function may have neuroprotective effects [153]. AKT has also been identified as a regulator of Nav channels 1.1 [120] and 1.6 [160]. In the case of Nav1.1, it is observed that AKT directly phosphorylates the channel, resulting in decreased channel activity [120]. However, in CA1 pyramidal cells, Akt inhibition with triciribine results in increased action potential firing, which is likely driven by Nav1.6 [160]. This may be a result of direct interactions between AKT and Nav1.6 or a downstream effect of decreased activation of glycogen synthase kinase 3β (GSK3β), which phosphorylates the Nav1.6 channel at its T1936 residue [115], potentiating its activity. Moreover, GSK3β displays dysregulated function and increased expression in the hippocampus of AD patients and rodent models [161,162,163,164]. Therefore, in CA1 pyramidal neurons, activation of AKT may exert neuroprotective effects by reducing GSK3b activity, thereby decreasing Nav1.6 activity. However, considering the dichotomous effects of AKT activation on Nav1.1 [120] and 1.6 [160], inhibition of the downstream interaction between Nav1.6 and GSK3β may serve as a more viable approach than functional modulation of AKT activity.

5.2. Modulation of Nav Channel Macromolecular Complexes

In addition to regulation via phosphorylation, the Nav channel function is also modulated via stable interactions with other ChAPs [113,114,118]. One subclass of these accessory proteins that have been investigated for their ability to regulate Nav channel activity is the intracellular fibroblast growth factors (iFGFs) [95,117,123,165]. These proteins are a subset of the FGF superfamily and include FGF11, FGF12, FGF13, and FGF14 [166]. The iFGFs are expressed in excitable cells, where they are able to modulate the activity of Nav channels through stable interactions with their intracellular C-terminal domains [166]. Intriguingly, interactions of the iFGFs with Nav channels diverge among Nav and iFGF isoforms, resulting in an array of functional outcomes [113]. Despite this complexity, the divergence in cell-type expression among Nav channel isoforms may allow for fine-tuning of channel properties, and thus neuronal excitability, via modulating iFGF/Nav interfaces in target tissues. Of particular interest, FGF14 has been identified as a risk factor for AD [167,168]. In hippocampal neurons, it is observed that FGF14 overexpression results in a significant increase in Nav1.6 current densities, whereas genetic knockdown of FGF14 results in opposing phenotypes and decreased excitability [169]. Moreover, studies from our lab have illustrated that the FGF14/Nav channel complex is a target of GSK3β [170] and that pharmacological inhibition of GSK3β induces dissociation of the FGF14/Nav complex in hippocampal neurons and modifies FGF14-mediated modulation of Nav channel activity [170]. Further investigation revealed that GSK3β phosphorylates FGF14 at S226 and that phosphorylation of this residue is increased in Tg2576 AD rodents [171]. Moreover, alanine mutation of the S226 residue results in decreased complex formation with Nav1.6 [171]. As described in the previous section, GSK3β is a serine-threonine kinase with dysregulated activity and expression in the hippocampus of AD brains [161,162,163,164]. Thus, hyperphosphorylation of FGF14 by GSK3β may lead to a significantly increased probability of FGF14/Nav1.6 complex formation in early AD, thereby potentiating Nav1.6 activity and aberrant neuronal hyperexcitability in CA1 neurons. Further investigation is required to determine the precise mechanisms of phosphorylation-driven regulation of the FGF14/Nav1.6 complex, but disruption of FGF14 binding to the channel directly in the hippocampus of AD brains may prevent its potentiation of Nav1.6-mediated neuronal excitability and aid in ameliorating hippocampal network hyperactivity.

6. Conclusions

There remains a major need for AD therapeutics with disease-modifying properties. Therefore, elucidating the neuronal mechanisms that underlie AD progression is a critical step in the development of novel interventions. Hippocampal hyperactivity is one of the first neuronal phenotypes observed in AD patients, and it is linked to the onset of memory deficits as well progression of AD pathophysiology. Correction of this hyperactivity, therefore, is an attractive disease-modifying therapeutic strategy and has emerged as the focus of many recent investigations. While the complete roles of Nav1.1 and Nav1.6 throughout AD progression remain to be elucidated, their contributions to early-stage hyperactivity are under investigation and may prove critical to the development of disease-modifying AD therapeutics. Given their central roles in governing the excitability of these neuronal subtypes, functional modulation of Nav1.1 and Nav1.6 represents a promising therapeutic strategy to regulate hippocampal activity in early-stage AD, and their contributions to early-stage hyperactivity may prove critical to the development of disease-modifying AD therapeutics. In addition to pursuing traditional pharmacological approaches, Nav channel activity may be regulated through modulation of post-translational modifications or stable interactions with auxiliary proteins that alter channel activity. In the AD brain, there are numerous kinase signaling cascades and disease-related proteins that exhibit distinct functions and expression patterns during disease progression, several of which have established functional effects on Nav channels. In many cases, the functional consequences of these interactions are divergent among Nav isoforms. Therefore, functionally modulating Nav channels through altering their regulatory PTMs or protein complexes may provide the opportunity for the development of isoform-specific Nav channel therapeutics with improved specificity for diseased tissues.

Author Contributions

Conceptualization, T.J.B. and F.L.; writing—original draft preparation, T.J.B., N.A.G., Z.H. and P.A.; writing—review and editing, T.J.B., N.M.D. and F.L.; supervision, F.L.; funding acquisition, T.J.B., N.M.D. and F.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Institutes of Health grants R01MH124351, R01ES031823, R01 MH132226 and R01ES031823-03S1 (F.L.); the training program funded by the National Institute of Aging (NIH Grant # T32AG067952-01; T.J.B.); and the Houston Area Molecular Biophysics Program Grant No. T32 GM008280 (N.M.D).

Data Availability Statement

No new data was created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

Schematics in this review were generated using BioRender.

Conflicts of Interest

F.L. is the founder and president of IonTx Inc., a start-up company focusing on developing regulators of voltage-gated Na+ channels.

References

  1. Nisbet, R.M.; Götz, J. Amyloid-β and Tau in Alzheimer’s Disease: Novel Pathomechanisms and Non-Pharmacological Treatment Strategies. J. Alzheimers Dis. 2018, 64, S517–S527. [Google Scholar] [CrossRef] [PubMed]
  2. U. F. O. Themes. The Practical Pharmacology of Donepezil. Basicmedical Key, 21 August 2016. Available online: https://basicmedicalkey.com/the-practical-pharmacology-of-donepezil/ (accessed on 25 July 2023).
  3. Guo, J.; Wang, Z.; Liu, R.; Huang, Y.; Zhang, N.; Zhang, R. Memantine, Donepezil, or Combination Therapy—What is the best therapy for Alzheimer’s Disease? A Network Meta-Analysis. Brain Behav. 2020, 10, e01831. [Google Scholar] [CrossRef] [PubMed]
  4. Padda, I.S.; Parmar, M. Aducanumab. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2023. Available online: http://www.ncbi.nlm.nih.gov/books/NBK573062/ (accessed on 25 July 2023).
  5. van Dyck, C.H.; Swanson, C.J.; Aisen, P.; Bateman, R.J.; Chen, C.; Gee, M.; Kanekiyo, M.; Li, D.; Reyderman, L.; Cohen, S.; et al. Lecanemab in Early Alzheimer’s Disease. N. Engl. J. Med. 2023, 388, 9–21. [Google Scholar] [CrossRef] [PubMed]
  6. Devi, G.; Scheltens, P. Heterogeneity of Alzheimer’s disease: Consequence for drug trials? Alzheimers Res. Ther. 2018, 10, 122. [Google Scholar] [CrossRef]
  7. Jack, C.R.; Bennett, D.A.; Blennow, K.; Carrillo, M.C.; Dunn, B.; Haeberlein, S.B.; Holtzman, D.M.; Jagust, W.; Jessen, F.; Karlawish, J.; et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s Dement. 2018, 14, 535–562. [Google Scholar] [CrossRef] [PubMed]
  8. Grothe, M.J.; Barthel, H.; Sepulcre, J.; Dyrba, M.; Sabri, O.; Teipel, S.J. In vivo staging of regional amyloid deposition. Neurology 2017, 89, 2031–2038. [Google Scholar] [CrossRef]
  9. Kaufman, S.K.; Del Tredici, K.; Thomas, T.L.; Braak, H.; Diamond, M.I. Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART. Acta Neuropathol. 2018, 136, 57–67. [Google Scholar] [CrossRef]
  10. Iaccarino, L.; Tammewar, G.; Ayakta, N.; Baker, S.L.; Bejanin, A.; Boxer, A.L.; Gorno-Tempini, M.L.; Janabi, M.; Kramer, J.H.; Lazaris, A.; et al. Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer’s Disease. NeuroImage Clin. 2017, 17, 452–464. [Google Scholar] [CrossRef]
  11. Bolmont, T.; Clavaguera, F.; Meyer-Luehmann, M.; Herzig, M.C.; Radde, R.; Staufenbiel, M.; Lewis, J.; Hutton, M.; Tolnay, M.; Jucker, M. Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am. J. Pathol. 2007, 171, 2012–2020. [Google Scholar] [CrossRef]
  12. Vasconcelos, B.; Stancu, I.-C.; Buist, A.; Bird, M.; Wang, P.; Vanoosthuyse, A.; Van Kolen, K.; Verheyen, A.; Kienlen-Campard, P.; Octave, J.-N.; et al. Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo. Acta Neuropathol. 2016, 131, 549–569. [Google Scholar] [CrossRef]
  13. Stancu, I.-C.; Vasconcelos, B.; Terwel, D.; Dewachter, I. Models of β-amyloid induced Tau-pathology: The long and “folded” road to understand the mechanism. Mol. Neurodegener. 2014, 9, 51. [Google Scholar] [CrossRef] [PubMed]
  14. Pooler, A.M.; Polydoro, M.; Maury, E.A.; Nicholls, S.B.; Reddy, S.M.; Wegmann, S.; William, C.; Saqran, L.; Cagsal-Getkin, O.; Pitstick, R.; et al. Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease. Acta Neuropathol. Commun. 2015, 3, 14. [Google Scholar] [CrossRef] [PubMed]
  15. Mijalkov, M.; Volpe, G.; Fernaud-Espinosa, I.; DeFelipe, J.; Pereira, J.B.; Merino-Serrais, P. Dendritic spines are lost in clusters in Alzheimer’s disease. Sci. Rep. 2021, 11, 12350. [Google Scholar] [CrossRef]
  16. Griffiths, J.; Grant, S.G.N. Synapse pathology in Alzheimer’s disease. Semin. Cell Dev. Biol. 2023, 139, 13–23. [Google Scholar] [CrossRef]
  17. Benarroch, E.E. Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease: Emerging mechanisms. Neurology 2018, 91, 125–132. [Google Scholar] [CrossRef] [PubMed]
  18. Busche, M.A.; Chen, X.; Henning, H.A.; Reichwald, J.; Staufenbiel, M.; Sakmann, B.; Konnerth, A. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2012, 109, 8740–8745. [Google Scholar] [CrossRef]
  19. Šišková, Z.; Justus, D.; Kaneko, H.; Friedrichs, D.; Henneberg, N.; Beutel, T.; Pitsch, J.; Schoch, S.; Becker, A.; von der Kammer, H.; et al. Dendritic Structural Degeneration Is Functionally Linked to Cellular Hyperexcitability in a Mouse Model of Alzheimer’s Disease. Neuron 2014, 84, 1023–1033. [Google Scholar] [CrossRef]
  20. Kazim, S.F.; Chuang, S.-C.; Zhao, W.; Wong, R.K.S.; Bianchi, R.; Iqbal, K. Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade. Front. Aging Neurosci. 2017, 9, 71. [Google Scholar] [CrossRef]
  21. Lee-Liu, D.; Gonzalez-Billault, C. Neuron-intrinsic origin of hyperexcitability during early pathogenesis of Alzheimer’s disease. J. Neurochem. 2021, 158, 586–588. [Google Scholar] [CrossRef]
  22. Celone, K.A.; Calhoun, V.D.; Dickerson, B.C.; Atri, A.; Chua, E.F.; Miller, S.L.; DePeau, K.; Rentz, D.M.; Selkoe, D.J.; Blacker, D.; et al. Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer’s Disease: An Independent Component Analysis. J. Neurosci. 2006, 26, 10222–10231. [Google Scholar] [CrossRef]
  23. Filippini, N.; MacIntosh, B.J.; Hough, M.G.; Goodwin, G.M.; Frisoni, G.B.; Smith, S.M.; Matthews, P.M.; Beckmann, C.F.; Mackay, C.E. Distinct patterns of brain activity in young carriers of the APOE-ε4 allele. Proc. Natl. Acad. Sci. USA 2009, 106, 7209–7214. [Google Scholar] [CrossRef] [PubMed]
  24. Bassett, S.S.; Yousem, D.M.; Cristinzio, C.; Kusevic, I.; Yassa, M.A.; Caffo, B.S.; Zeger, S.L. Familial risk for Alzheimer’s disease alters fMRI activation patterns. Brain 2006, 129, 1229–1239. [Google Scholar] [CrossRef] [PubMed]
  25. Hämäläinen, A.; Pihlajamäki, M.; Tanila, H.; Hänninen, T.; Niskanen, E.; Tervo, S.; Karjalainen, P.A.; Vanninen, R.L.; Soininen, H. Increased fMRI responses during encoding in mild cognitive impairment. Neurobiol. Aging 2007, 28, 1889–1903. [Google Scholar] [CrossRef] [PubMed]
  26. Dickerson, B.C.; Salat, D.H.; Greve, D.N.; Chua, E.F.; Rand-Giovannetti, E.; Rentz, D.M.; Bertram, L.; Mullin, K.; Tanzi, R.E.; Blacker, D.; et al. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology 2005, 65, 404–411. [Google Scholar] [CrossRef] [PubMed]
  27. Toniolo, S.; Sen, A.; Husain, M. Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease. Int. J. Mol. Sci. 2020, 21, 9318. [Google Scholar] [CrossRef]
  28. Setti, S.E.; Hunsberger, H.C.; Reed, M.N. Alterations in Hippocampal Activity and Alzheimer’s Disease. Transl. Issues Psychol. Sci. 2017, 3, 348–356. [Google Scholar] [CrossRef]
  29. Ciccone, R.; Franco, C.; Piccialli, I.; Boscia, F.; Casamassa, A.; de Rosa, V.; Cepparulo, P.; Cataldi, M.; Annunziato, L.; Pannaccione, A. Amyloid β-Induced Upregulation of Nav1.6 Underlies Neuronal Hyperactivity in Tg2576 Alzheimer’s Disease Mouse Model. Sci. Rep. 2019, 9, 13592. [Google Scholar] [CrossRef]
  30. Vico Varela, E.; Etter, G.; Williams, S. Excitatory-inhibitory imbalance in Alzheimer’s disease and therapeutic significance. Neurobiol. Dis. 2019, 127, 605–615. [Google Scholar] [CrossRef]
  31. Targa Dias Anastacio, H.; Matosin, N.; Ooi, L. Neuronal hyperexcitability in Alzheimer’s disease: What are the drivers behind this aberrant phenotype? Transl. Psychiatry 2022, 12, 257. [Google Scholar] [CrossRef]
  32. Bakker, A.; Krauss, G.L.; Albert, M.S.; Speck, C.L.; Jones, L.R.; Stark, C.E.; Yassa, M.A.; Bassett, S.S.; Shelton, A.L.; Gallagher, M. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 2012, 74, 467–474. [Google Scholar] [CrossRef]
  33. Leal, S.L.; Landau, S.M.; Bell, R.K.; Jagust, W.J. Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline. Elife 2017, 6, e22978. [Google Scholar] [CrossRef] [PubMed]
  34. Yuan, D.; Yang, G.; Wu, W.; Li, Q.; Xu, D.; Ntim, M.; Jiang, C.; Liu, J.; Zhang, Y.; Wang, Y.; et al. Reducing Nav1.6 expression attenuates the pathogenesis of Alzheimer’s disease by suppressing BACE1 transcription. Aging Cell 2022, 21, e13593. [Google Scholar] [CrossRef] [PubMed]
  35. Gail Canter, R.; Huang, W.-C.; Choi, H.; Wang, J.; Ashley Watson, L.; Yao, C.G.; Abdurrob, F.; Bousleiman, S.M.; Young, J.Z.; Bennett, D.A.; et al. 3D mapping reveals network-specific amyloid progression and subcortical susceptibility in mice. Commun. Biol. 2019, 2, 360. [Google Scholar] [CrossRef] [PubMed]
  36. Cirrito, J.R.; Yamada, K.A.; Finn, M.B.; Sloviter, R.S.; Bales, K.R.; May, P.C.; Schoepp, D.D.; Paul, S.M.; Mennerick, S.; Holtzman, D.M. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 2005, 48, 913–922. [Google Scholar] [CrossRef]
  37. Yamamoto, K.; Tanei, Z.-I.; Hashimoto, T.; Wakabayashi, T.; Okuno, H.; Naka, Y.; Yizhar, O.; Fenno, L.E.; Fukayama, M.; Bito, H.; et al. Chronic optogenetic activation augments aβ pathology in a mouse model of Alzheimer disease. Cell Rep. 2015, 11, 859–865. [Google Scholar] [CrossRef]
  38. Pooler, A.M.; Phillips, E.C.; Lau, D.H.W.; Noble, W.; Hanger, D.P. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 2013, 14, 389–394. [Google Scholar] [CrossRef]
  39. Tse, M.T. Anti-epileptic drug shows benefit in AD mouse model. Nat. Rev. Drug Discov. 2012, 11, 748–749. [Google Scholar] [CrossRef]
  40. Sanchez, P.E.; Zhu, L.; Verret, L.; Vossel, K.A.; Orr, A.G.; Cirrito, J.R.; Devidze, N.; Ho, K.; Yu, G.-Q.; Palop, J.J.; et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc. Natl. Acad. Sci. USA 2012, 109, E2895–E2903. [Google Scholar] [CrossRef]
  41. Hu, W.; Tian, C.; Li, T.; Yang, M.; Hou, H.; Shu, Y. Distinct contributions of Nav1.6 and Nav1.2 in action potential initiation and backpropagation. Nat. Neurosci. 2009, 12, 996–1002. [Google Scholar] [CrossRef]
  42. Catterall, W.A. Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy. Neurochem. Res. 2017, 42, 2495–2504. [Google Scholar] [CrossRef]
  43. Booker, S.A.; Vida, I. Morphological diversity and connectivity of hippocampal interneurons. Cell Tissue Res. 2018, 373, 619–641. [Google Scholar] [CrossRef] [PubMed]
  44. Gloveli, T.; Kopell, N.; Dugladze, T. Neuronal Activity Patterns During Hippocampal Network Oscillations In Vitro. In Hippocampal Microcircuits: A Computational Modeler’s Resource Book; Cutsuridis, V., Graham, B., Cobb, S., Vida, I., Eds.; Springer Series in Computational Neuroscience; Springer: New York, NY, USA, 2010; pp. 247–276. ISBN 978-1-4419-0996-1. [Google Scholar]
  45. Kowalski, J.; Gan, J.; Jonas, P.; Pernía-Andrade, A.J. Intrinsic membrane properties determine hippocampal differential firing pattern in vivo in anesthetized rats. Hippocampus 2016, 26, 668–682. [Google Scholar] [CrossRef]
  46. Chauhan, P.; Jethwa, K.; Rathawa, A.; Chauhan, G.; Mehra, S. The Anatomy of the Hippocampus. In Cerebral Ischemia; Pluta, R., Ed.; Exon Publications: Brisbane, Australia, 2021; ISBN 978-0-645-00179-2. [Google Scholar]
  47. Stepan, J.; Dine, J.; Eder, M. Functional optical probing of the hippocampal trisynaptic circuit in vitro: Network dynamics, filter properties, and polysynaptic induction of CA1 LTP. Front. Neurosci. 2015, 9, 160. [Google Scholar] [CrossRef] [PubMed]
  48. Sosa, M.; Gillespie, A.K.; Frank, L.M. Neural Activity Patterns Underlying Spatial Coding in the Hippocampus. Curr. Top. Behav. Neurosci. 2018, 37, 43–100. [Google Scholar] [CrossRef]
  49. Pelkey, K.A.; Chittajallu, R.; Craig, M.T.; Tricoire, L.; Wester, J.C.; McBain, C.J. Hippocampal GABAergic Inhibitory Interneurons. Physiol. Rev. 2017, 97, 1619–1747. [Google Scholar] [CrossRef] [PubMed]
  50. Pouille, F.; Scanziani, M. Enforcement of Temporal Fidelity in Pyramidal Cells by Somatic Feed-Forward Inhibition. Science 2001, 293, 1159–1163. [Google Scholar] [CrossRef] [PubMed]
  51. Ferguson, B.R.; Gao, W.-J. PV Interneurons: Critical Regulators of E/I Balance for Prefrontal Cortex-Dependent Behavior and Psychiatric Disorders. Front. Neural Circuits 2018, 12, 37. [Google Scholar] [CrossRef]
  52. Sadeh, S.; Clopath, C. Excitatory-inhibitory balance modulates the formation and dynamics of neuronal assemblies in cortical networks. Sci. Adv. 2021, 7, eabg8411. [Google Scholar] [CrossRef]
  53. de Lera Ruiz, M.; Kraus, R.L. Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications. J. Med. Chem. 2015, 58, 7093–7118. [Google Scholar] [CrossRef]
  54. Royeck, M.; Horstmann, M.-T.; Remy, S.; Reitze, M.; Yaari, Y.; Beck, H. Role of axonal NaV1.6 sodium channels in action potential initiation of CA1 pyramidal neurons. J. Neurophysiol. 2008, 100, 2361–2380. [Google Scholar] [CrossRef]
  55. Wang, J.; Ou, S.-W.; Wang, Y.-J. Distribution and function of voltage-gated sodium channels in the nervous system. Channels 2017, 11, 534–554. [Google Scholar] [CrossRef] [PubMed]
  56. Duflocq, A.; Le Bras, B.; Bullier, E.; Couraud, F.; Davenne, M. Nav1.1 is predominantly expressed in nodes of Ranvier and axon initial segments. Mol. Cell. Neurosci. 2008, 39, 180–192. [Google Scholar] [CrossRef] [PubMed]
  57. Catterall, W.A.; Kalume, F.; Oakley, J.C. NaV1.1 channels and epilepsy. J. Physiol. 2010, 588, 1849–1859. [Google Scholar] [CrossRef] [PubMed]
  58. Cheah, C.S.; Yu, F.H.; Westenbroek, R.E.; Kalume, F.K.; Oakley, J.C.; Potter, G.B.; Rubenstein, J.L.; Catterall, W.A. Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome. Proc. Natl. Acad. Sci. USA 2012, 109, 14646–14651. [Google Scholar] [CrossRef]
  59. Zybura, A.; Hudmon, A.; Cummins, T.R. Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability. Cells 2021, 10, 1595. [Google Scholar] [CrossRef]
  60. Martinez-Losa, M.; Tracy, T.E.; Ma, K.; Verret, L.; Clemente-Perez, A.; Khan, A.S.; Cobos, I.; Ho, K.; Gan, L.; Mucke, L.; et al. Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer’s Disease. Neuron 2018, 98, 75–89.e5. [Google Scholar] [CrossRef]
  61. DeFelipe, J.; López-Cruz, P.L.; Benavides-Piccione, R.; Bielza, C.; Larrañaga, P.; Anderson, S.; Burkhalter, A.; Cauli, B.; Fairén, A.; Feldmeyer, D.; et al. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat. Rev. Neurosci. 2013, 14, 202–216. [Google Scholar] [CrossRef]
  62. Wonders, C.P.; Anderson, S.A. The origin and specification of cortical interneurons. Nat. Rev. Neurosci. 2006, 7, 687–696. [Google Scholar] [CrossRef]
  63. Ogiwara, I.; Miyamoto, H.; Morita, N.; Atapour, N.; Mazaki, E.; Inoue, I.; Takeuchi, T.; Itohara, S.; Yanagawa, Y.; Obata, K.; et al. Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying an Scn1a Gene Mutation. J. Neurosci. 2007, 27, 5903–5914. [Google Scholar] [CrossRef]
  64. Wang, W.; Takashima, S.; Segawa, Y.; Itoh, M.; Shi, X.; Hwang, S.-K.; Nabeshima, K.; Takeshita, M.; Hirose, S. The developmental changes of Na(v)1.1 and Na(v)1.2 expression in the human hippocampus and temporal lobe. Brain Res. 2011, 1389, 61–70. [Google Scholar] [CrossRef]
  65. Ding, J.; Li, X.; Tian, H.; Wang, L.; Guo, B.; Wang, Y.; Li, W.; Wang, F.; Sun, T. SCN1A Mutation—Beyond Dravet Syndrome: A Systematic Review and Narrative Synthesis. Front. Neurol. 2021, 12, 743726. [Google Scholar] [CrossRef] [PubMed]
  66. Vossel, K.A.; Beagle, A.J.; Rabinovici, G.D.; Shu, H.; Lee, S.E.; Naasan, G.; Hegde, M.; Cornes, S.B.; Henry, M.L.; Nelson, A.B.; et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013, 70, 1158–1166. [Google Scholar] [CrossRef] [PubMed]
  67. Csernus, E.A.; Werber, T.; Kamondi, A.; Horvath, A.A. The Significance of Subclinical Epileptiform Activity in Alzheimer’s Disease: A Review. Front. Neurol. 2022, 13, 856500. [Google Scholar] [CrossRef] [PubMed]
  68. Hamm, V.; Héraud, C.; Bott, J.-B.; Herbeaux, K.; Strittmatter, C.; Mathis, C.; Goutagny, R. Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer’s disease. Sci. Adv. 2017, 3, e1601068. [Google Scholar] [CrossRef]
  69. Hu, T.; Xiao, Z.; Mao, R.; Chen, B.; Lu, M.-N.; Tong, J.; Mei, R.; Li, S.-S.; Xiao, Z.-C.; Zhang, L.-F.; et al. Navβ2 knockdown improves cognition in APP/PS1 mice by partially inhibiting seizures and APP amyloid processing. Oncotarget 2017, 8, 99284–99295. [Google Scholar] [CrossRef] [PubMed]
  70. Verret, L.; Mann, E.O.; Hang, G.B.; Barth, A.M.I.; Cobos, I.; Ho, K.; Devidze, N.; Masliah, E.; Kreitzer, A.C.; Mody, I.; et al. Inhibitory Interneuron Deficit Links Altered Network Activity and Cognitive Dysfunction in Alzheimer Model. Cell 2012, 149, 708–721. [Google Scholar] [CrossRef]
  71. Rossor, M.N.; Garrett, N.J.; Johnson, A.L.; Mountjoy, C.Q.; Roth, M.; Iversen, L.L. A post-mortem study of the cholinergic and GABA systems in senile dementia. Brain J. Neurol. 1982, 105, 313–330. [Google Scholar] [CrossRef]
  72. Pike, C.J.; Cotman, C.W. Cultured GABA-immunoreactive neurons are resistant to toxicity induced by beta-amyloid. Neuroscience 1993, 56, 269–274. [Google Scholar] [CrossRef]
  73. Blazquez-Llorca, L. Pericellular innervation of neurons expressing abnormally hyperphosphorylated tau in the hippocampal formation of Alzheimer’s disease patients. Front. Neuroanat. 2010, 4, 20. [Google Scholar] [CrossRef]
  74. Huang, Y.; Mucke, L. Alzheimer Mechanisms and Therapeutic Strategies. Cell 2012, 148, 1204–1222. [Google Scholar] [CrossRef] [PubMed]
  75. Govindpani, K.; Calvo-Flores Guzmán, B.; Vinnakota, C.; Waldvogel, H.J.; Faull, R.L.; Kwakowsky, A. Towards a Better Understanding of GABAergic Remodeling in Alzheimer’s Disease. Int. J. Mol. Sci. 2017, 18, 1813. [Google Scholar] [CrossRef] [PubMed]
  76. Selkoe, D.J. Early network dysfunction in Alzheimer’s disease. Science 2019, 365, 540–541. [Google Scholar] [CrossRef] [PubMed]
  77. Villette, V.; Dutar, P. GABAergic Microcircuits in Alzheimer’s Disease Models. Curr. Alzheimer Res. 2017, 14, 30–39. [Google Scholar] [CrossRef]
  78. Kim, D.Y.; Carey, B.W.; Wang, H.; Ingano, L.A.M.; Binshtok, A.M.; Wertz, M.H.; Pettingell, W.H.; He, P.; Lee, V.M.-Y.; Woolf, C.J.; et al. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat. Cell Biol. 2007, 9, 755–764. [Google Scholar] [CrossRef] [PubMed]
  79. Tyler, S.J.; Dawbarn, D.; Wilcock, G.K.; Allen, S.J. alpha- and beta-secretase: Profound changes in Alzheimer’s disease. Biochem. Biophys. Res. Commun. 2002, 299, 373–376. [Google Scholar] [CrossRef] [PubMed]
  80. Fukumoto, H.; Cheung, B.S.; Hyman, B.T.; Irizarry, M.C. β-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease. Arch. Neurol. 2002, 59, 1381–1389. [Google Scholar] [CrossRef]
  81. Yang, L.-B.; Lindholm, K.; Yan, R.; Citron, M.; Xia, W.; Yang, X.-L.; Beach, T.; Sue, L.; Wong, P.; Price, D.; et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat. Med. 2003, 9, 3–4. [Google Scholar] [CrossRef]
  82. Caccavano, A.; Bozzelli, P.L.; Forcelli, P.A.; Pak, D.T.S.; Wu, J.-Y.; Conant, K.; Vicini, S. Inhibitory Parvalbumin Basket Cell Activity is Selectively Reduced during Hippocampal Sharp Wave Ripples in a Mouse Model of Familial Alzheimer’s Disease. J. Neurosci. 2020, 40, 5116–5136. [Google Scholar] [CrossRef]
  83. Briend, F.; Nelson, E.A.; Maximo, O.; Armstrong, W.P.; Kraguljac, N.V.; Lahti, A.C. Hippocampal glutamate and hippocampus subfield volumes in antipsychotic-naive first episode psychosis subjects and relationships to duration of untreated psychosis. Transl. Psychiatry 2020, 10, 137. [Google Scholar] [CrossRef]
  84. van Dijk, R.M.; Huang, S.-H.; Slomianka, L.; Amrein, I. Taxonomic Separation of Hippocampal Networks: Principal Cell Populations and Adult Neurogenesis. Front. Neuroanat. 2016, 10, 22. Available online: https://www.frontiersin.org/articles/10.3389/fnana.2016.00022 (accessed on 25 July 2023).
  85. Erickson, A.; Deiteren, A.; Harrington, A.M.; Garcia-Caraballo, S.; Castro, J.; Caldwell, A.; Grundy, L.; Brierley, S.M. Voltage-gated sodium channels: (NaV)igating the field to determine their contribution to visceral nociception. J. Physiol. 2018, 596, 785–807. [Google Scholar] [CrossRef] [PubMed]
  86. Kaplan, M.R.; Cho, M.-H.; Ullian, E.M.; Isom, L.L.; Levinson, S.R.; Barres, B.A. Differential Control of Clustering of the Sodium Channels Nav1.2 and Nav1.6 at Developing CNS Nodes of Ranvier. Neuron 2001, 30, 105–119. [Google Scholar] [CrossRef] [PubMed]
  87. Tapia, C.M.; Folorunso, O.; Singh, A.K.; McDonough, K.; Laezza, F. Effects of Deltamethrin Acute Exposure on Nav1.6 Channels and Medium Spiny Neurons of the Nucleus Accumbens. Toxicology 2020, 440, 152488. [Google Scholar] [CrossRef]
  88. Solé, L.; Wagnon, J.L.; Tamkun, M.M. Functional analysis of three Nav1.6 mutations causing early infantile epileptic encephalopathy. Biochim. Biophys. Acta BBA Mol. Basis Dis. 2020, 1866, 165959. [Google Scholar] [CrossRef] [PubMed]
  89. Alrashdi, B.; Dawod, B.; Schampel, A.; Tacke, S.; Kuerten, S.; Marshall, J.S.; Côté, P.D. Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis. J. Neuroinflamm. 2019, 16, 215. [Google Scholar] [CrossRef]
  90. Wagnon, J.L.; Barker, B.S.; Ottolini, M.; Park, Y.; Volkheimer, A.; Valdez, P.; Swinkels, M.E.M.; Patel, M.K.; Meisler, M.H. Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol. Genet. 2017, 3, e170. [Google Scholar] [CrossRef]
  91. Hargus, N.J.; Nigam, A.; Bertram, E.H.; Patel, M.K. Evidence for a role of Nav1.6 in facilitating increases in neuronal hyperexcitability during epileptogenesis. J. Neurophysiol. 2013, 110, 1144–1157. [Google Scholar] [CrossRef]
  92. Li, S.; Wang, X.; Ma, Q.-H.; Yang, W.; Zhang, X.-G.; Dawe, G.S.; Xiao, Z.-C. Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway. Sci. Rep. 2016, 6, 39320. [Google Scholar] [CrossRef]
  93. Liu, C.; Tan, F.C.K.; Xiao, Z.-C.; Dawe, G.S. Amyloid precursor protein enhances Nav1.6 sodium channel cell surface expression. J. Biol. Chem. 2015, 290, 12048–12057. [Google Scholar] [CrossRef]
  94. Ren, S.; Chen, P.; Jiang, H.; Mi, Z.; Xu, F.; Hu, B.; Zhang, J.; Zhu, Z. Persistent sodium currents contribute to Aβ1-42-induced hyperexcitation of hippocampal CA1 pyramidal neurons. Neurosci. Lett. 2014, 580, 62–67. [Google Scholar] [CrossRef]
  95. Dvorak, N.M.; Wadsworth, P.A.; Wang, P.; Zhou, J.; Laezza, F. Development of Allosteric Modulators of Voltage-Gated Na+ Channels: A Novel Approach for an Old Target. Curr. Top. Med. Chem. 2021, 21, 841–848. [Google Scholar] [CrossRef] [PubMed]
  96. Southwell, D.G.; Nicholas, C.R.; Basbaum, A.I.; Stryker, M.P.; Kriegstein, A.R.; Rubenstein, J.L.; Alvarez-Buylla, A. Interneurons from Embryonic Development to Cell-Based Therapy. Science 2014, 344, 1240622. [Google Scholar] [CrossRef] [PubMed]
  97. Martier, R.; Konstantinova, P. Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock. Front. Neurosci. 2020, 14, 580179. [Google Scholar] [CrossRef]
  98. Snowball, A.; Schorge, S. Changing channels in pain and epilepsy: Exploiting ion channel gene therapy for disorders of neuronal hyperexcitability. FEBS Lett. 2015, 589, 1620–1634. [Google Scholar] [CrossRef] [PubMed]
  99. Dey, D.; Eckle, V.-S.; Vitko, I.; Sullivan, K.A.; Lasiecka, Z.M.; Winckler, B.; Stornetta, R.L.; Williamson, J.M.; Kapur, J.; Perez-Reyes, E. A potassium leak channel silences hyperactive neurons and ameliorates status epilepticus. Epilepsia 2014, 55, 203–213. [Google Scholar] [CrossRef]
  100. Wykes, R.C.; Heeroma, J.H.; Mantoan, L.; Zheng, K.; MacDonald, D.C.; Deisseroth, K.; Hashemi, K.S.; Walker, M.C.; Schorge, S.; Kullmann, D.M. Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy. Sci. Transl. Med. 2012, 4, 161ra152. [Google Scholar] [CrossRef]
  101. Nguyen, H.X.; Wu, T.; Needs, D.; Zhang, H.; Perelli, R.M.; DeLuca, S.; Yang, R.; Tian, M.; Landstrom, A.P.; Henriquez, C.; et al. Engineered bacterial voltage-gated sodium channel platform for cardiac gene therapy. Nat. Commun. 2022, 13, 620. [Google Scholar] [CrossRef]
  102. Jensen, H.S.; Grunnet, M.; Bastlund, J.F. Therapeutic potential of NaV1.1 activators. Trends Pharmacol. Sci. 2014, 35, 113–118. [Google Scholar] [CrossRef]
  103. James, T.F.; Nenov, M.N.; Tapia, C.M.; Lecchi, M.; Koshy, S.; Green, T.A.; Laezza, F. Consequences of acute Nav1.1 exposure to deltamethrin. Neurotoxicology 2017, 60, 150–160. [Google Scholar] [CrossRef]
  104. Osteen, J.D.; Herzig, V.; Gilchrist, J.; Emrick, J.J.; Zhang, C.; Wang, X.; Castro, J.; Garcia-Caraballo, S.; Grundy, L.; Rychkov, G.Y.; et al. Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature 2016, 534, 494–499. [Google Scholar] [CrossRef]
  105. Richards, K.L.; Milligan, C.J.; Richardson, R.J.; Jancovski, N.; Grunnet, M.; Jacobson, L.H.; Undheim, E.A.B.; Mobli, M.; Chow, C.Y.; Herzig, V.; et al. Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death. Proc. Natl. Acad. Sci. USA 2018, 115, E8077–E8085. [Google Scholar] [CrossRef]
  106. Chow, C.Y.; Chin, Y.K.Y.; Ma, L.; Undheim, E.A.B.; Herzig, V.; King, G.F. A selective NaV1.1 activator with potential for treatment of Dravet syndrome epilepsy. Biochem. Pharmacol. 2020, 181, 113991. [Google Scholar] [CrossRef] [PubMed]
  107. Crestey, F.; Frederiksen, K.; Jensen, H.S.; Dekermendjian, K.; Larsen, P.H.; Bastlund, J.F.; Lu, D.; Liu, H.; Yang, C.R.; Grunnet, M.; et al. Identification and Electrophysiological Evaluation of 2-Methylbenzamide Derivatives as Nav1.1 Modulators. ACS Chem. Neurosci. 2015, 6, 1302–1308. [Google Scholar] [CrossRef] [PubMed]
  108. Miyazaki, T.; Kawasaki, M.; Suzuki, A.; Ito, Y.; Imanishi, A.; Maru, T.; Kawamoto, T.; Koike, T. Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Nav1.1 activators. Bioorg. Med. Chem. Lett. 2019, 29, 815–820. [Google Scholar] [CrossRef]
  109. Klitgaard, H. Levetiracetam: The preclinical profile of a new class of antiepileptic drugs? Epilepsia 2001, 42 (Suppl. S4), 13–18. [Google Scholar] [CrossRef]
  110. Johnson, J.; Focken, T.; Khakh, K.; Tari, P.K.; Dube, C.; Goodchild, S.J.; Andrez, J.-C.; Bankar, G.; Bogucki, D.; Burford, K.; et al. NBI-921352, a first-in-class, NaV1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats. Elife 2022, 11, e72468. [Google Scholar] [CrossRef]
  111. Beatch, G.; Namdari, R.; Cadieux, J.; Kato, H.; Aycardi, E. A Phase 1 Study to Assess the Safety, Tolerability and Pharmacokinetics of Two Formulations of a Novel Nav1.6 Sodium Channnel Blocker (XEN901) in Healthy Adult Subjects. Neurology 2020, 94, 4757. [Google Scholar]
  112. Pitt, G.S.; Lee, S.-Y. Current view on regulation of voltage-gated sodium channels by calcium and auxiliary proteins. Protein Sci. 2016, 25, 1573–1584. [Google Scholar] [CrossRef] [PubMed]
  113. Laezza, F.; Lampert, A.; Kozel, M.A.; Gerber, B.R.; Rush, A.M.; Nerbonne, J.M.; Waxman, S.G.; Dib-Hajj, S.D.; Ornitz, D.M. FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels. Mol. Cell. Neurosci. 2009, 42, 90–101. [Google Scholar] [CrossRef]
  114. Effraim, P.R.; Huang, J.; Lampert, A.; Stamboulian, S.; Zhao, P.; Black, J.A.; Dib-Hajj, S.D.; Waxman, S.G. Fibroblast growth factor homologous factor 2 (FGF-13) associates with Nav1.7 in DRG neurons and alters its current properties in an isoform-dependent manner. Neurobiol. Pain 2019, 6, 100029. [Google Scholar] [CrossRef]
  115. Scala, F.; Nenov, M.N.; Crofton, E.J.; Singh, A.K.; Folorunso, O.; Zhang, Y.; Chesson, B.C.; Wildburger, N.C.; James, T.F.; Alshammari, M.A.; et al. Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway. Cell Rep. 2018, 23, 555–567. [Google Scholar] [CrossRef] [PubMed]
  116. Lou, J.-Y.; Laezza, F.; Gerber, B.R.; Xiao, M.; Yamada, K.A.; Hartmann, H.; Craig, A.M.; Nerbonne, J.M.; Ornitz, D.M. Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels. J. Physiol. 2005, 569, 179–193. [Google Scholar] [CrossRef] [PubMed]
  117. Dvorak, N.M.; Wadsworth, P.A.; Wang, P.; Chen, H.; Zhou, J.; Laezza, F. Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics. Molecules 2020, 25, 3365. [Google Scholar] [CrossRef] [PubMed]
  118. Ali, S.R.; Liu, Z.; Nenov, M.N.; Folorunso, O.; Singh, A.; Scala, F.; Chen, H.; James, T.F.; Alshammari, M.; Panova-Elektronova, N.I.; et al. Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic. ACS Chem. Neurosci. 2018, 9, 976–987. [Google Scholar] [CrossRef]
  119. Wadsworth, P.A.; Singh, A.K.; Nguyen, N.; Dvorak, N.M.; Tapia, C.M.; Russell, W.K.; Stephan, C.; Laezza, F. JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation. Biochim. Biophys. Acta Mol. Cell Res. 2020, 1867, 118786. [Google Scholar] [CrossRef]
  120. Arribas-Blázquez, M.; Piniella, D.; Olivos-Oré, L.A.; Bartolomé-Martín, D.; Leite, C.; Giménez, C.; Artalejo, A.R.; Zafra, F. Regulation of the voltage-dependent sodium channel NaV1.1 by AKT1. Neuropharmacology 2021, 197, 108745. [Google Scholar] [CrossRef]
  121. Zybura, A.S.; Baucum, A.J.; Rush, A.M.; Cummins, T.R.; Hudmon, A. CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability. J. Biol. Chem. 2020, 295, 11845–11865. [Google Scholar] [CrossRef]
  122. Gasser, A.; Cheng, X.; Gilmore, E.S.; Tyrrell, L.; Waxman, S.G.; Dib-Hajj, S.D. Two Nedd4-binding Motifs Underlie Modulation of Sodium Channel Nav1.6 by p38 MAPK. J. Biol. Chem. 2010, 285, 26149–26161. [Google Scholar] [CrossRef]
  123. Singh, A.K.; Wadsworth, P.A.; Tapia, C.M.; Aceto, G.; Ali, S.R.; Chen, H.; D’Ascenzo, M.; Zhou, J.; Laezza, F. Mapping of the FGF14:Nav1.6 complex interface reveals FLPK as a functionally active peptide modulating excitability. Physiol. Rep. 2020, 8, e14505. [Google Scholar] [CrossRef]
  124. Chakroborty, S.; Briggs, C.; Miller, M.B.; Goussakov, I.; Schneider, C.; Kim, J.; Wicks, J.; Richardson, J.C.; Conklin, V.; Cameransi, B.G.; et al. Stabilizing ER Ca2+ Channel Function as an Early Preventative Strategy for Alzheimer’s Disease. PLoS ONE 2012, 7, e52056. [Google Scholar] [CrossRef]
  125. Berridge, M.J. Calcium hypothesis of Alzheimer’s disease. Pflügers Arch. Eur. J. Physiol. 2010, 459, 441–449. [Google Scholar] [CrossRef] [PubMed]
  126. Fukushima, H.; Maeda, R.; Suzuki, R.; Suzuki, A.; Nomoto, M.; Toyoda, H.; Wu, L.-J.; Xu, H.; Zhao, M.-G.; Ueda, K.; et al. Upregulation of calcium/calmodulin-dependent protein kinase IV improves memory formation and rescues memory loss with aging. J. Neurosci. 2008, 28, 9910–9919. [Google Scholar] [CrossRef] [PubMed]
  127. Ghosh, A.; Giese, K.P. Calcium/calmodulin-dependent kinase II and Alzheimer’s disease. Mol. Brain 2015, 8, 78. [Google Scholar] [CrossRef] [PubMed]
  128. Oddo, S.; Caccamo, A.; Shepherd, J.D.; Murphy, M.P.; Golde, T.E.; Kayed, R.; Metherate, R.; Mattson, M.P.; Akbari, Y.; LaFerla, F.M. Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles. Neuron 2003, 39, 409–421. [Google Scholar] [CrossRef] [PubMed]
  129. Foster, T.C.; Kyritsopoulos, C.; Kumar, A. Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer’s disease. Behav. Brain Res. 2017, 322, 223–232. [Google Scholar] [CrossRef]
  130. Anekonda, T.S.; Quinn, J.F.; Harris, C.; Frahler, K.; Wadsworth, T.L.; Woltjer, R.L. L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer’s disease. Neurobiol. Dis. 2011, 41, 62–70. [Google Scholar] [CrossRef]
  131. Junho, C.V.C.; Caio-Silva, W.; Trentin-Sonoda, M.; Carneiro-Ramos, M.S. An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome. Front. Physiol. 2020, 11, 735. Available online: https://www.frontiersin.org/articles/10.3389/fphys.2020.00735 (accessed on 25 July 2023). [CrossRef]
  132. O’Day, D.H.; Eshak, K.; Myre, M.A. Calmodulin Binding Proteins and Alzheimer’s Disease. J. Alzheimers Dis. 2015, 46, 553–569. [Google Scholar] [CrossRef]
  133. Wang, Y.-J.; Chen, G.-H.; Hu, X.-Y.; Lu, Y.-P.; Zhou, J.-N.; Liu, R.-Y. The expression of calcium/calmodulin-dependent protein kinase II-α in the hippocampus of patients with Alzheimer’s disease and its links with AD-related pathology. Brain Res. 2005, 1031, 101–108. [Google Scholar] [CrossRef]
  134. Chang, J.-Y.; Parra-Bueno, P.; Laviv, T.; Szatmari, E.M.; Lee, S.-J.R.; Yasuda, R. CaMKII Autophosphorylation is Necessary for Optimal Integration of Ca2+ Signals During LTP Induction but Not Maintenance. Neuron 2017, 94, 800–808.e4. [Google Scholar] [CrossRef]
  135. Thompson, C.H.; Hawkins, N.A.; Kearney, J.A.; George, A.L. CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice. Proc. Natl. Acad. Sci. USA 2017, 114, 1696–1701. [Google Scholar] [CrossRef] [PubMed]
  136. Ashpole, N.M.; Herren, A.W.; Ginsburg, K.S.; Brogan, J.D.; Johnson, D.E.; Cummins, T.R.; Bers, D.M.; Hudmon, A. Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Regulates Cardiac Sodium Channel NaV1.5 Gating by Multiple Phosphorylation Sites. J. Biol. Chem. 2012, 287, 19856–19869. [Google Scholar] [CrossRef] [PubMed]
  137. Zybura, A.S.; Sahoo, F.K.; Hudmon, A.; Cummins, T.R. CaMKII Inhibition Attenuates Distinct Gain-of-Function Effects Produced by Mutant Nav1.6 Channels and Reduces Neuronal Excitability. Cells 2022, 11, 2108. [Google Scholar] [CrossRef] [PubMed]
  138. Turjanski, A.G.; Vaqué, J.P.; Gutkind, J.S. MAP kinases and the control of nuclear events. Oncogene 2007, 26, 3240–3253. [Google Scholar] [CrossRef]
  139. Arthur, J.S.C.; Ley, S.C. Mitogen-activated protein kinases in innate immunity. Nat. Rev. Immunol. 2013, 13, 679–692. [Google Scholar] [CrossRef] [PubMed]
  140. Morrison, D.K. MAP Kinase Pathways. Cold Spring Harb. Perspect. Biol. 2012, 4, a011254. [Google Scholar] [CrossRef]
  141. Asih, P.R.; Prikas, E.; Stefanoska, K.; Tan, A.R.P.; Ahel, H.I.; Ittner, A. Functions of p38 MAP Kinases in the Central Nervous System. Front. Mol. Neurosci. 2020, 13, 570586. [Google Scholar] [CrossRef]
  142. Bolshakov, V.Y.; Carboni, L.; Cobb, M.H.; Siegelbaum, S.A.; Belardetti, F. Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3-CA1 synapses. Nat. Neurosci. 2000, 3, 1107–1112. [Google Scholar] [CrossRef]
  143. Bhaskar, K.; Konerth, M.; Kokiko-Cochran, O.N.; Cardona, A.; Ransohoff, R.M.; Lamb, B.T. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 2010, 68, 19–31. [Google Scholar] [CrossRef] [PubMed]
  144. Zhu, X.; Rottkamp, C.A.; Hartzler, A.; Sun, Z.; Takeda, A.; Boux, H.; Shimohama, S.; Perry, G.; Smith, M.A. Activation of MKK6, an upstream activator of p38, in Alzheimer’s disease. J. Neurochem. 2001, 79, 311–318. [Google Scholar] [CrossRef]
  145. Feijoo, C.; Campbell, D.G.; Jakes, R.; Goedert, M.; Cuenda, A. Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. J. Cell Sci. 2005, 118, 397–408. [Google Scholar] [CrossRef] [PubMed]
  146. Maphis, N.; Jiang, S.; Xu, G.; Kokiko-Cochran, O.N.; Roy, S.M.; Van Eldik, L.J.; Watterson, D.M.; Lamb, B.T.; Bhaskar, K. Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology. Alzheimers Res. Ther. 2016, 8, 54. [Google Scholar] [CrossRef] [PubMed]
  147. Ittner, A.; Chua, S.W.; Bertz, J.; Volkerling, A.; van der Hoven, J.; Gladbach, A.; Przybyla, M.; Bi, M.; van Hummel, A.; Stevens, C.H.; et al. Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice. Science 2016, 354, 904–908. [Google Scholar] [CrossRef] [PubMed]
  148. Rutigliano, G.; Stazi, M.; Arancio, O.; Watterson, D.M.; Origlia, N. An isoform-selective p38α mitogen-activated protein kinase inhibitor rescues early entorhinal cortex dysfunctions in a mouse model of Alzheimer’s disease. Neurobiol. Aging 2018, 70, 86–91. [Google Scholar] [CrossRef] [PubMed]
  149. Roy, S.M.; Grum-Tokars, V.L.; Schavocky, J.P.; Saeed, F.; Staniszewski, A.; Teich, A.F.; Arancio, O.; Bachstetter, A.D.; Webster, S.J.; Van Eldik, L.J.; et al. Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer’s disease mouse models. ACS Chem. Neurosci. 2015, 6, 666–680. [Google Scholar] [CrossRef] [PubMed]
  150. Wittmack, E.K.; Rush, A.M.; Hudmon, A.; Waxman, S.G.; Dib-Hajj, S.D. Voltage-Gated Sodium Channel Nav1.6 Is Modulated by p38 Mitogen-Activated Protein Kinase. J. Neurosci. 2005, 25, 6621–6630. [Google Scholar] [CrossRef]
  151. Liu, X.; Zhang, L.; Zhang, H.; Liang, X.; Zhang, B.; Tu, J.; Zhao, Y. Nedd4-2 Haploinsufficiency in Mice Impairs the Ubiquitination of Rer1 and Increases the Susceptibility to Endoplasmic Reticulum Stress and Seizures. Front. Mol. Neurosci. 2022, 15, 919718. [Google Scholar] [CrossRef]
  152. Kitagishi, Y.; Kobayashi, M.; Kikuta, K.; Matsuda, S. Roles of PI3K/AKT/GSK3/mTOR Pathway in Cell Signaling of Mental Illnesses. Depress. Res. Treat. 2012, 2012, 752563. [Google Scholar] [CrossRef]
  153. Kumar, M.; Bansal, N. Implications of Phosphoinositide 3-Kinase-Akt (PI3K-Akt) Pathway in the Pathogenesis of Alzheimer’s Disease. Mol. Neurobiol. 2022, 59, 354–385. [Google Scholar] [CrossRef]
  154. Long, H.-Z.; Cheng, Y.; Zhou, Z.-W.; Luo, H.-Y.; Wen, D.-D.; Gao, L.-C. PI3K/AKT Signal Pathway: A Target of Natural Products in the Prevention and Treatment of Alzheimer’s Disease and Parkinson’s Disease. Front. Pharmacol. 2021, 12, 648636. Available online: https://www.frontiersin.org/articles/10.3389/fphar.2021.648636 (accessed on 25 July 2023).
  155. Sato, A.; Sunayama, J.; Matsuda, K.; Tachibana, K.; Sakurada, K.; Tomiyama, A.; Kayama, T.; Kitanaka, C. Regulation of neural stem/progenitor cell maintenance by PI3K and mTOR. Neurosci. Lett. 2010, 470, 115–120. [Google Scholar] [CrossRef] [PubMed]
  156. Horwood, J.M.; Dufour, F.; Laroche, S.; Davis, S. Signalling mechanisms mediated by the phosphoinositide 3-kinase/Akt cascade in synaptic plasticity and memory in the rat. Eur. J. Neurosci. 2006, 23, 3375–3384. [Google Scholar] [CrossRef] [PubMed]
  157. Wang, Q.; Liu, L.; Pei, L.; Ju, W.; Ahmadian, G.; Lu, J.; Wang, Y.; Liu, F.; Wang, Y.T. Control of synaptic strength, a novel function of Akt. Neuron 2003, 38, 915–928. [Google Scholar] [CrossRef]
  158. Yin, G.; Li, L.-Y.; Qu, M.; Luo, H.-B.; Wang, J.-Z.; Zhou, X.-W. Upregulation of AKT Attenuates Amyloid-β-Induced Cell Apoptosis. J. Alzheimers Dis. 2011, 25, 337–345. [Google Scholar] [CrossRef] [PubMed]
  159. Mackenzie, R.W.; Elliott, B.T. Akt/PKB activation and insulin signaling: A novel insulin signaling pathway in the treatment of type 2 diabetes. Diabetes Metab. Syndr. Obes. Targets Ther. 2014, 7, 55–64. [Google Scholar] [CrossRef] [PubMed]
  160. Marosi, M.; Nenov, M.N.; Di Re, J.; Dvorak, N.M.; Alshammari, M.; Laezza, F. Inhibition of the Akt/PKB Kinase Increases Nav1.6-Mediated Currents and Neuronal Excitability in CA1 Hippocampal Pyramidal Neurons. Int. J. Mol. Sci. 2022, 23, 1700. [Google Scholar] [CrossRef]
  161. Leroy, K.; Yilmaz, Z.; Brion, J.-P. Increased level of active GSK-3beta in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol. Appl. Neurobiol. 2007, 33, 43–55. [Google Scholar] [CrossRef]
  162. Beurel, E.; Grieco, S.F.; Jope, R.S. Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases. Pharmacol. Ther. 2015, 148, 114–131. [Google Scholar] [CrossRef]
  163. D’Mello, S.R. When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease. Int. J. Mol. Sci. 2021, 22, 5911. [Google Scholar] [CrossRef]
  164. Hooper, C.; Killick, R.; Lovestone, S. The GSK3 hypothesis of Alzheimer’s disease. J. Neurochem. 2008, 104, 1433–1439. [Google Scholar] [CrossRef]
  165. Hsu, W.-C.; Nenov, M.N.; Shavkunov, A.; Panova, N.; Zhan, M.; Laezza, F. Identifying a Kinase Network Regulating FGF14:Nav1.6 Complex Assembly Using Split-Luciferase Complementation. PLoS ONE 2015, 10, e0117246. [Google Scholar] [CrossRef]
  166. Pablo, J.L.; Pitt, G.S. Fibroblast growth factor homologous factors (FHFs): New roles in neuronal health and disease. Neuroscientist 2016, 22, 19–25. [Google Scholar] [CrossRef]
  167. Antonell, A.; Lladó, A.; Altirriba, J.; Botta-Orfila, T.; Balasa, M.; Fernández, M.; Ferrer, I.; Sánchez-Valle, R.; Molinuevo, J.L. A preliminary study of the whole-genome expression profile of sporadic and monogenic early-onset Alzheimer’s disease. Neurobiol. Aging 2013, 34, 1772–1778. [Google Scholar] [CrossRef] [PubMed]
  168. Di Re, J.; Wadsworth, P.A.; Laezza, F. Intracellular Fibroblast Growth Factor 14: Emerging Risk Factor for Brain Disorders. Front. Cell. Neurosci. 2017, 11, 103. [Google Scholar] [CrossRef] [PubMed]
  169. Goldfarb, M.; Schoorlemmer, J.; Williams, A.; Diwakar, S.; Wang, Q.; Huang, X.; Giza, J.; Tchetchik, D.; Kelley, K.; Vega, A.; et al. Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage gated sodium channels. Neuron 2007, 55, 449–463. [Google Scholar] [CrossRef] [PubMed]
  170. Shavkunov, A.S.; Wildburger, N.C.; Nenov, M.N.; James, T.F.; Buzhdygan, T.P.; Panova-Elektronova, N.I.; Green, T.A.; Veselenak, R.L.; Bourne, N.; Laezza, F. The Fibroblast Growth Factor 14·Voltage-gated Sodium Channel Complex is a New Target of Glycogen Synthase Kinase 3 (GSK3). J. Biol. Chem. 2013, 288, 19370–19385. [Google Scholar] [CrossRef]
  171. Hsu, W.-C.J.; Wildburger, N.C.; Haidacher, S.J.; Nenov, M.N.; Folorunso, O.; Singh, A.K.; Chesson, B.C.; Franklin, W.F.; Cortez, I.; Sadygov, R.G.; et al. PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer’s disease. Exp. Neurol. 2017, 295, 1–17. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Article Metrics

Citations

Article Access Statistics

Journal Statistics
Multiple requests from the same IP address are counted as one view.
Download PDF
Antioxidant and Anti-Inflammatory Activities of Stellera chamaejasme L. Roots and Aerial Parts Extracts
Previous
Dietary Implications of Polyunsaturated Fatty Acids during Pregnancy and in Neonates
Next