Search Results (393)

Calcium (Ca²⁺)signaling dysfunction is a central contributor to neuronal hyperexcitability and seizure propagation in epilepsy, yet the intracellular mechanisms underlying the actions of valproic acid (VPA) remain incompletely understood. In this study, we investigated whether VPA modulates Ca²⁺ homeostasis at the level of the endoplasmic reticulum (ER) and how this action influences cytosolic Ca²⁺ dynamics associated with epileptiform activity. ER Ca²⁺ levels were directly measured using ER-targeted aequorin in HeLa and PC12 cells, while cytosolic Ca²⁺ signals were monitored by fura-2 fluorescence imaging in bovine chromaffin cells exposed to veratridine, a model of sustained sodium channel activation and Ca²⁺ oscillations. VPA induced a concentration-dependent release of Ca²⁺ from the ER, with an IC₅₀ of approximately 17 µM. This effect was preserved in permeabilized cells and exhibited activation kinetics comparable to those elicited by inositol 1,4,5-trisphosphate (InsP₃). Pharmacological inhibition of InsP₃ receptors (InsP₃Rs), but not ryanodine receptors or SERCA, abolished VPA-induced ER Ca²⁺ release, supporting a selective InsP₃R-mediated mechanism. Functionally, VPA suppressed the repetitive cytosolic Ca²⁺ oscillations induced by veratridine, while simultaneously producing a sustained elevation of cytosolic Ca²⁺ originating from ER stores and facilitating depolarization-evoked catecholamine secretion. Together, these results support the conclusion that VPA induces InsP₃R-mediated Ca²⁺ mobilization from the endoplasmic reticulum and identify ER Ca²⁺ release as a previously unrecognized intracellular mechanism contributing to its modulatory effects on Ca²⁺ signaling and excitability in epilepsy. Full article

Acid-sensing ion channels (ASICs), activated under acidic conditions, play a critical role in ischemic brain injury, but the detailed mechanisms and signaling pathways remain unclear. Our previous studies have shown that activation of ASIC1a channels contributes to acidosis-induced neuronal injury, partially mediated by increased calcium influx. In this study, we provide evidence that activation of ASIC2a-containing channels induces zinc influx. In cultured mouse cortical neurons, ASIC currents that were insensitive to PcTx1 inhibition were potentiated by extracellular zinc. In Chinese Hamster Ovary cells transfected with different ASIC subunits, large inward currents were recorded upon a pH drop from 7.4 to 5.0 in cells expressing homomeric ASIC1a, ASIC2a, or heteromeric ASIC1a/2a channels when normal Na⁺-rich extracellular fluid (ECF) was used. However, when ECF was modified to one containing zinc as the primary cation, the same pH drop induced an inward current only in cells expressing homomeric ASIC2a or heteromeric ASIC1a/2a, but not homomeric ASIC1a. Fluorescence imaging revealed rapid zinc influx in cells expressing ASIC2a but not ASIC1a when zinc was applied with the acidic ECF. Additionally, at pH values where ASIC2a-containing channels were activated, acid-mediated neurotoxicity was exacerbated by zinc. Thus, ASIC2a-containing channels may represent a novel pathway for zinc entry and activation of these channels might contribute to zinc-mediated neurotoxicity. Full article

Neuronal synapses are the functional units of communication in the central nervous system. This review describes the molecular mechanisms regulating synaptic transmission, plasticity, and circuit refinement. At the presynaptic active zone, scaffolding proteins including bassoon, piccolo, RIMs, and munc13 organize vesicle priming and the localization of voltage-gated calcium channels. Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1. Following exocytosis, synaptic vesicles are recovered through clathrin-mediated, ultrafast, bulk, or kiss-and-run endocytic pathways. Postsynaptically, the postsynaptic density (PSD) serves as a protein hub where scaffolds such as PSD-95, shank, homer, and gephyrin anchor excitatory (AMPA, NMDA) and inhibitory (GABA-A, Glycine) receptors are observed. Synaptic strength is modified during long-term potentiation (LTP) and depression (LTD) through signaling cascades involving kinases like CaMKII, PKA, and PKC, or phosphatases such as PP1 and calcineurin. These pathways regulate receptor trafficking, Arc-mediated endocytosis, and actin-dependent remodeling of dendritic spines. Additionally, synapse formation and elimination are guided by cell adhesion molecules, including neurexins and neuroligins, and by microglial pruning via the complement cascade (C1q, C3) and “don’t eat me” signals like CD47. Molecular diversity is further expanded by alternative splicing and post-translational modifications. A unified model of synaptic homeostasis is required to understand the basis of neuropsychiatric and neurological disorders. Full article

Excitable neurons are intrinsically capable of firing action potentials (AP), yet a state of hyperexcitability is prevented in the central nervous system by powerful GABAergic inhibition. For this inhibition to be effective, it must occur before excitatory signals can initiate runaway activity, implying the existence of a proactive control system. To test for such proactive inhibition, we used Ca²⁺ imaging and patch-clamp recording to measure how hippocampal neurons respond to depolarization and glutamatergic agonists. In mature hippocampal cultures (14 days in vitro (DIV)) and acute brain slices from two-month-old rats, neurons exhibited non-simultaneous responses to various excitatory stimuli, including KCl, NH₄Cl, forskolin, domoic acid, and glutamate. We observed that the Ca²⁺ rise occurred significantly earlier in GABAergic neurons than in glutamatergic neurons. This delay in glutamatergic neurons was abolished by GABA(A) receptor inhibitors, suggesting a mechanism of preliminary γ-aminobutyric acid (GABA) release. We further found that these early-responding GABAergic neurons express calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs). Application of domoic acid induced an immediate Ca²⁺ increase in neurons expressing these receptors, but a delayed response in others. Crucially, when domoic acid was applied in the presence of the AMPA receptor inhibitors NBQX or GYKI-52466, the response delay in glutamatergic neurons was significantly prolonged. This confirms that CP-KARs on GABAergic neurons are responsible for the delayed excitation of glutamatergic neurons. In hippocampal slices from two-month-old rats, depolarization with 50 mM KCl revealed two distinct neuronal populations based on their calcium dynamics: a majority group (presumably glutamatergic) exhibited fluctuating Ca²⁺ signals, while a minority (presumably GABAergic) showed a steady, advancing increase in [Ca²⁺]i. This distinction was reinforced by the application of domoic acid. The “advancing-response” neurons reacted to domoic acid with a similar prompt increase, whereas the “fluctuating-response” neurons displayed an even more delayed and fluctuating reaction (80 s delay). Therefore, we identify a subgroup of hippocampal neurons—in both slices and cultures—that respond to depolarization and domoic acid with an early [Ca²⁺]_i signal. Consistent with our data from cultures, we conclude these early-responding neurons are GABAergic. Their early GABA release directly explains the delayed Ca²⁺ response observed in glutamatergic neurons. We propose that this proactive mechanism, mediated by CP-KARs on GABAergic neurons, is a primary means of protecting the network from hyperexcitation. Furthermore, the activity of these CP-KAR-expressing neurons is itself regulated by GABAergic neurons containing CP-AMPARs. Full article

Calcium ions (Ca²⁺) serve as universal second messengers regulating endocrine, neuronal, and metabolic processes. In children and adolescents, tight calcium signaling control is crucial for growth, hormone homeostasis, neuromuscular function, and neurodevelopment. Disruptions in Ca²⁺-dependent pathways—whether genetic, metabolic, or acquired—underlie a spectrum of pediatric endocrine diseases often presenting with neurological manifestations This review summarizes calcium’s roles in hormone secretion, parathyroid and vitamin D metabolism, and neuronal excitability, and discusses monogenic and metabolic disorders affecting calcium sensing and signaling, including CASR, GNA11, AP2S1, STIM1, and ORAI1 mutations. Diagnostic challenges, therapeutic strategies, and future directions for precision medicine in pediatric neuroendocrinology are highlighted, emphasizing early recognition and improved clinical outcomes. Full article

Brain tumors, particularly glioblastoma, remain among the most lethal cancers, with limited survival benefits from current genetic and molecular-targeted approaches. Emerging evidence reveals that beyond oncogenes and mutations, neuronal plasticity, long-term potentiation, synaptic remodeling, and neurotransmitter-driven signaling play a pivotal role in shaping tumor progression and therapeutic response. This convergence of neuroscience and oncology has given rise to the field of cancer neuroscience, which explores the bidirectional interactions between neurons and malignant cells. In this review, we summarize fundamental principles of neuronal plasticity, contrasting physiological roles with pathological reprogramming in brain tumors. We highlight how tumor cells exploit synaptic input, particularly glutamatergic signaling, to enhance proliferation, invasion, and integration into neural circuits. We further discuss how neuronal-driven feedback loops contribute to therapy resistance, including chemoresistance, radioresistance, and immune evasion, mediated through pathways such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and calcium influx. The tumor microenvironment, including astrocytes, microglia, and oligodendrocyte-lineage cells, emerges as an active participant in reinforcing this neuron-tumor ecosystem. Finally, this review explores therapeutic opportunities targeting neuronal plasticity, spanning pharmacological interventions, neuromodulation approaches (transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), optogenetics), and computational/artificial intelligence frameworks that model neuron tumor networks to predict personalized therapy. Also, we propose future directions integrating connect omics, neuroinformatics, and brain organoid models to refine translational strategies. Full article

Cerebral ischemia–reperfusion injury triggers mitochondrial dysfunction and oxidative stress, exacerbating neuronal apoptosis. Emerging evidence highlights hydrogen sulfide (H₂S) as a gasotransmitter modulating redox balance, autophagy, and apoptosis. This study investigates the neuroprotective mechanisms of Enriched Environment (EE) against ischemic injury, focusing on mitochondrial dynamics and H₂S-mediated pathways. Using MCAO mice and OGD/R-treated SH-SY5Y neurons, interventions targeting H₂S synthesis, hypoxia-inducible factor 1-alpha (HIF-1α), and mitophagy were implemented. Behavioral, histological, and molecular analyses demonstrated EE significantly improved neurological outcomes, suppressed apoptosis, and attenuated oxidative damage (reduced MDA, elevated MnSOD/glutathione). Mechanistically, EE enhanced mitophagy via dual pathways: canonical PINK1/parkin-mediated mitochondrial clearance, corroborated by transmission electron microscope and LC3B/parkin colocalization, and non-canonical HIF-1α/BNIP3L axis activation. Transcriptomic and Co-immunoprecipitation (Co-IP) data revealed EE upregulated endogenous H₂S biosynthesis post-injury by promoting dopamine-induced calcium influx, which activated calmodulin-dependent signaling to stimulate cystathionine β-synthase/γ-lyase expression. Pharmacological blockade of H₂S synthesis or HIF-1α abolished mitochondrial protection, confirming H₂S as a central mediator. Notably, H₂S exerted antiapoptotic effects by restoring mitochondrial integrity through synergistic mitophagy activation and oxidative stress mitigation. These findings propose a novel neuroprotective cascade: EE-induced dopaminergic signaling potentiates H₂S production, which coordinates PINK1/parkin and HIF-1α/BNIP3L pathways to eliminate dysfunctional mitochondria, thereby preserving neuronal homeostasis. This study elucidates therapeutic potential of EE via H₂S-driven mitochondrial quality control, offering insights for ischemic brain injury intervention. Full article

Thought processes in the brain occur as it continually modifies its use of energy. This review integrates research findings from molecular neurology, vascular physiology and non-equilibrium thermodynamics to create a comprehensive perspective on thinking as a coordinated energy process. Data shows that there is a relationship between the processing of information and metabolism throughout all scales, from the mitochondria’s electron transport chain to the rhythmic changes in the microvasculature. Through the cellular level of organization, mitochondrial networks, calcium (Ca²⁺) signals from astrocytes and the adaptive control of capillaries work together to maintain a state of balance between order and dissipation that maintains function while also maintaining the ability to be flexible. The longer-term regulatory mechanisms including redox plasticity, epigenetic programs and organelle remodeling may convert short-lived states of metabolism into long-lasting physiological “memory”. As well, data indicates that the cortical networks of the brain appear to be operating close to their critical regimes, which will allow them to respond to stimuli but prevent the brain from reaching an unstable energetic state. It is suggested that cognition occurs as the result of the brain’s ability to coordinate energy supply with neural activity over both time and space. Providing a perspective of the functional aspects of neurons as a continuous thermodynamic process creates a framework for making predictive statements that will guide future studies to measure coherence as a key link between energy flow, perception, memory and cognition. Full article

Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in clinical development for Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). The S1R is a ubiquitous chaperone protein enriched in the central nervous system and regulates multiple pathways critical for neuronal cell function and survival, including cellular stress responses, mitochondrial function, calcium signaling, protein folding, and autophagy. S1R has a crucial role in the ER mitochondria-associated membrane (MAM), whose dysfunction is implicated in several neurodegenerative diseases. By activating the S1R, pridopidine corrects multiple cellular pathways necessary to the cell’s ability to respond to stress, which are disrupted in neurodegenerative diseases. Pridopidine restores MAM integrity; rescues Ca²⁺ homeostasis and autophagy; mitigates ER stress, mitochondrial dysfunction, and oxidative damage; and enhances brain-derived neurotrophic factor (BDNF) axonal transport and secretion, synaptic plasticity, and dendritic spine density. Pridopidine demonstrates neuroprotective effects in in vivo models of neurodegenerative diseases (NDDs). Importantly, pridopidine demonstrates the biphasic dose response characteristic of S1R agonists. In clinical trials in HD and ALS, pridopidine has shown benefits across multiple endpoints. Pridopidine’s mechanism of action, modulating core cellular survival pathways, positions it as a promising candidate for disease modification for different nervous system disorders. Its broad therapeutic potential includes neurodevelopmental disorders, and rare diseases including Wolfram syndrome, Rett syndrome, and Vanishing White Matter Disease. Here, we review the experimental data demonstrating pridopidine’s S1R-mediated neuroprotective effects. These findings underscore the therapeutic relevance of S1R activation and support further investigation of pridopidine for the treatment of different neurodegenerative diseases including ALS and HD. Full article

Astrocytes, long viewed as passive support cells, are now recognized as dynamic regulators of synaptic function. This mini review summarizes recent findings revealing that astrocyte leaflets, thin peripheral processes of astrocyte, form gap junction interconnected domains containing tiny endoplasmic reticulum saccules. Interestingly, the astrocyte leaflets directly contact and enwrap 90% of neuron synapses in clusters. Furthermore, neuronal circuit activity could trigger local Ca²⁺ dynamics in astrocyte leaflets mediated by inositol 1,4,5-trisphosphate receptor type 1 (IP₃R1), while leaflet Ca²⁺ signals could integrate neuronal circuits active at different spatiotemporal scales. These findings uncover the novel glial-synapse interactions and highlight the pathophysiological roles of astrocyte leaflets in neuron circuit computation, relevant to human neurological diseases (NDs). In addition, therapeutic opportunities, such as targeting leaflet calcium signaling for neuroprotection, alongside challenges in imaging and modeling are discussed. Future perspectives emphasize advanced tools like optogenetics and artificial intelligence to unravel astrocyte contributions, paving the way for glial-centric interventions in NDs. Full article

Migraine is characterized by severe pain and somatic symptoms like allodynia and photophobia, driven by neuroinflammation that sensitizes the trigeminal vascular system (TVS). This study investigated how neuroinflammation induced by systemic lipopolysaccharide (LPS) affects migraine-related nociceptive signaling. Using a chronic migraine model in rats with nitroglycerin (NTG), we compared prenatal and acute postnatal LPS administration. Rats with prenatal LPS exhibited lower mechanical thresholds and enhanced allodynia and photophobia after NTG. Acute LPS also increased allodynia, but not photophobia. Both LPS groups showed increased mast cell degranulation in the dura mater. Plasma CGRP after NTG administration was elevated in the acute LPS group. Electrophysiology revealed enhanced trigeminal afferent responses to serotonin in both acutely and prenatally LPS-treated rats. Calcium imaging demonstrated increased neuronal responses to serotonin and capsaicin, suggesting an upregulation of serotonin and TRPV1 receptors. Our findings show that LPS-induced neuroinflammation, whether prenatal or acute, promotes sensitization of peripheral and central nociceptive pathways, involving serotoninergic mechanisms. Full article

Astrocytes play a pivotal role in shaping synaptic function and in learning, memory, and emotion. Recent studies show that perisynaptic astrocytic processes form structured interactions with pre- and postsynaptic elements, which extends synaptic diversity beyond neuron–neuron connections. Accumulating evidence indicates that astrocytic Ca²⁺ signaling, gliotransmission, and local translation modulate synaptic efficacy and contribute to the formation and stabilization of memory traces. It is therefore essential to define how astrocytic microdomains, multisynaptic leaflet domains, and network-level ensembles cooperate to regulate circuit computation across space and time. Advances in super-resolution and volumetric in vivo imaging and spatial transcriptomics now enable detailed, cell-type- and compartment-specific analysis of astrocyte–synapse interactions in vivo. In this review, we highlight these approaches and synthesize classical and emerging mechanisms by which astrocytes read neuronal activity, write to synapses, and coordinate network states. We also discuss theoretical frameworks such as neuron–astrocyte associative memory models that formalize astrocytic calcium states as distributed substrates for storage and control. This integrated view provides new insight into the multicellular logic of memory and suggests paths toward understanding and treating neurological and psychiatric disorders. Full article

Neurodegenerative diseases pose a significant challenge to modern medicine. Despite significant advances in neurology, current therapeutic approaches often prove insufficient to treat such disorders. This study investigates the neuroprotective effect of extracellular vesicles derived from glial derivates of human-induced pluripotent stem cells. The extracellular vesicle’s cargo was characterised by proteomic analysis. The neuroprotective effect was assessed using a model of glutamate excitotoxicity performed on a primary culture of cortical neuroglial cells. The viability of cells was estimated using the MTT test and morphometric analyses. A comprehensive methodology was applied to investigate intracellular mechanisms, integrating assessments of intracellular calcium concentrations, mitochondrial membrane potential, and targeted inhibition of the PI3K-Akt pathway. Transcriptomic analysis of neuroglial cultures was used to validate the role of obtained mechanisms of extracellular vesicle’s neuroprotective effect. The obtaining results demonstrated the improvement of neuronal survival by reducing intracellular calcium levels and stabilising mitochondrial membrane potential under glutamate-induced excitotoxicity via PI3K-Akt signalling pathway activation. Moreover, the vesicles contained proteins that contribute to preventing apoptotic processes, activating regeneration of the nervous system, and modulating calcium ion transport and are associated with redox processes. Further transcriptomic analyses of neuroglial cultures treated with EVs showed an up-regulation of genes associated with regeneration, inhibition of calcium ion transport, regulation of membrane depolarisation, and negative regulation of apoptotic pathways. Full article

Astrocytes play a key role in maintaining redox balance and supporting neuronal survival within the central nervous system (CNS). Their antioxidant machinery, primarily involving the Nrf2–ARE (nuclear factor erythroid 2-related factor 2–antioxidant response element) pathway, glutathione (GSH) metabolism, and mitochondrial function, enables the removal of reactive oxygen and nitrogen species (ROS and RNS) and supports neuronal resistance to oxidative stress. Effective communication between neurons and astrocytes coordinates metabolic and antioxidative responses via glutamate-, nitric oxide-, and calcium-dependent signalling. Disruption of this crosstalk during traumatic injury, ischemia, or neurodegenerative disease causes redox imbalance, neuroinflammation, and excitotoxicity, which contribute to progressive neurodegeneration. Astrocytic Nrf2 activation reduces oxidative damage and inflammation, while its suppression encourages a neurotoxic glial phenotype. Current evidence emphasizes various therapeutic strategies targeting astrocytic redox mechanisms, including small-molecule Nrf2 activators, GSH precursors, mitochondria-targeted antioxidants (MTAs), and RNA- and gene-based approaches. These interventions boost the antioxidant ability of astrocytes, influence reactive cell phenotypes, and support neuronal recovery in preclinical models. Although there are still challenges in delivery and safety, restoring neuron–glia redox signalling offers a promising strategy for neuroprotective treatments aimed at reducing oxidative stress-related CNS injury and disease progression. Full article

Neuregulins (NRGs) are ligands of tyrosine kinase receptors from the ErbB family and play multiple developmental roles. NRG1–ErbB signaling regulates myelination and has been associated with amyotrophic lateral sclerosis (ALS) pathology. Given the potential therapeutic relevance of this pathway for motor neuron (MN) diseases, we employed a transgenic (TG) mouse with persistent neuronal overexpression of neuregulin type III (NRG1-III) to investigate its impact on the neuromuscular system. We performed an analysis of phenotypic changes in this TG model, including motor behavior, neuropathological evaluation by immunocytochemistry and ultrastructural examination of the spinal cord, peripheral nerves, and neuromuscular junctions (NMJs). Calcium dynamics in cultured MNs were also examined. We found that cholinergic C-boutons on TG MNs, where NRG1-III typically accumulates, exhibited upregulation of C-bouton-associated proteins and expansion of the subsynaptic cistern (SSC)-associated endoplasmic reticulum. Calcium imaging revealed altered homeostasis in TG MNs, accompanied by the upregulation of molecules linked to axonal plasticity. At NMJs, regressive changes involving autophagic dysregulation were observed. These alterations were accompanied by increased motor activity in behavioral tests. Overall, our findings indicate that persistently elevated NRG1-III signaling compromises MN connectivity and long-term health, a factor to consider when developing therapeutic strategies for neurodegenerative diseases such as ALS. Full article