Search Results (89)

Botulinum neurotoxins (BoNTs) are known to inhibit synaptic transmission by targeting SNARE proteins, but their selectivity toward central excitatory and inhibitory pathways is not yet fully understood. In this study, the interaction of serotypes A (BoNT/A) and B (BoNT/B) with the glutamatergic and GABAergic systems has been investigated using a pharmacological approach in an animal model of inflammatory pain, i.e., the formalin test in mice. BoNTs were administered intracerebroventricularly, three days before testing, followed 15 min before testing by systemic administration of sub-analgesic doses of MK801, an NMDA receptor antagonist, or muscimol, a GABA_A receptor agonist. BoNT/A reduced the second phase of the formalin test without affecting both the first phase and the interphase, suggesting a selective action on excitatory glutamatergic circuits while sparing GABAergic inhibition. Co-administration of MK801 with BoNT/A did not enhance analgesia, and muscimol did not further reduce interphase, confirming preserved GABAergic transmission. In contrast, BoNT/B abolished the interphase, consistent with impaired GABA release. Co-administration of MK801 or muscimol with BoNT/B restored the interphase, indicating compensatory rebalancing of excitatory-inhibitory networks. These results demonstrate that BoNT/A and BoNT/B exert distinct effects on central neurotransmission and support the hypothesis that BoNT/A preferentially targets excitatory synapses, while BoNT/B targets inhibitory synapses. This work contributes to a deeper understanding of anti-inflammatory mechanisms of BoNTs and their selective interaction with central pain pathways. Full article

Temperature is one of the critical factors influencing the survival, growth, and reproduction of organisms. The molting and developmental mechanisms of crustaceans are highly sensitive to temperature, yet the regulatory mechanisms underlying their thermal adaptation remain unclear. In this work, transcriptome sequencing was performed to analyze the gene expression profiles of Eriocheir sinensis under normal temperature (22 °C) and high-temperature (27 °C and 32 °C) conditions. A total of 377 differentially expressed genes (DEGs) were identified, including 149 up-regulated and 227 down-regulated genes. Through Gene Ontology (GO) enrichment analysis of these DEGs, 11 significantly temperature-regulated signaling pathways were identified, including the estrogen and androgen receptor signaling pathways, and two neurotransmission signaling pathways. These findings suggest that temperature may influence sex regulation in E. sinensis, while the dopamine receptor and neuropeptide signaling pathways may play a role in its thermal adaptation. Further validation via RT-qPCR of DEGs involved in neurotransmission signaling pathways revealed that crustacean hyperglycemic hormone (CHH) and excitatory amino acid transporter 3 (EAA3) genes are likely involved in the thermal adaptation of E. sinensis. In addition, the hemolymph glucose levels associated with the elevated temperatures were detected and consistent variations between glucose levels and CHH expressions were found. This indicates that the eyestalk CHH is strongly correlated with the hemolymph glucose levels and likely mediates the response to temperature changes by regulating blood glucose in E. sinensis. The results of this study not only provide key molecular targets for elucidating the mechanisms by which temperature affects molting and development in E. sinensis, but also establish a theoretical foundation for further research into thermal adaptation strategies in crustaceans. Full article

Synaptic plasticity is the key mechanism underlying learning and memory. Neurexins are pre-synaptic molecules that play a pivotal role in synaptic plasticity, interacting with many different post-synaptic molecules in the formation of neural circuits. Neurexins are alternatively spliced at different splice sites, yielding thousands of isoforms with different properties of interaction with post-synaptic molecules for a quick adaptation to internal and external inputs. The endocannabinoid system also plays a central role in synaptic plasticity, regulating key retrograde signaling at both excitatory and inhibitory synapses. This study aims at elucidating the crosstalk between alternative splicing of neurexin and the endocannabinoid system in the hippocampus. By employing an ex vivo hippocampal system, we found that pharmacological activation of cannabinoid receptor 1 (CB1) with the specific agonist ACEA led to reduced neurotransmission, associated with increased expression of the Nrxn1–3 spliced isoforms excluding the exon at splice site 4 (SS4−). In contrast, treatment with the CB1 antagonist AM251 increased glutamatergic activity and promoted the expression of the Nrxn variants including the exon (SS4+) Knockout of the involved splicing factor SLM2 determined the suppression of the exon splicing at SS4 and the expression only of the SS4+ variants of Nrxns1–3 transcripts. Interestingly, in SLM2 ko hippocampus, modulation of neurotransmission by AM251 or ACEA was abolished. These findings suggest a direct crosstalk between CB1-dependent signaling, neurotransmission and expression of specific Nrxns splice variants in the hippocampus. We propose that the fine-tuned regulation of Nrxn1–3 genes alternative splicing may play an important role in the feedback control of neurotransmission by the endocannabinoid system. Full article

Anesthesia is a cornerstone of modern medicine, enabling surgery, pain management, and critical care. Despite its widespread use, the precise molecular mechanisms of anesthetic action remain incompletely understood. Recent advancements in structural biology, including cryo-electron microscopy (Cryo-EM), X-ray crystallography, and computational modeling, have provided high-resolution insights into anesthetic–target interactions. This review examines key molecular targets, including GABA_A receptors, NMDA receptors, two-pore-domain potassium (K2P) channels (e.g., TREK-1), and voltage-gated sodium (Nav) channels. General anesthetics modulate GABA_A and NMDA receptors, affecting inhibitory and excitatory neurotransmission, while local anesthetics primarily block Nav channels, preventing action potential propagation. Structural studies have elucidated anesthetic binding sites and gating mechanisms, providing a foundation for drug optimization. Advances in computational drug design and AI-assisted modeling have accelerated the development of safer, more selective anesthetics, paving the way for precision anesthesia. Future research aims to develop receptor-subtype-specific anesthetics, Nav1.7-selective local anesthetics, and investigate the neural mechanisms of anesthesia-induced unconsciousness and postoperative cognitive dysfunction (POCD). By integrating structural biology, AI-driven drug discovery, and neuroscience, anesthesia research is evolving toward safer, more effective, and personalized strategies, enhancing clinical outcomes and patient safety. Full article

Recurrent and intense headache is a well appreciated cardinal feature of migraine, a common and incapacitating neurological disorder. Often, there are associated canonical sensory abnormalities, such as light and sound sensitivity, as well as associated nausea. Given this phenotype of disordered sensory processing and, in a third of patients, the phenomenon called aura accompanying migraine attacks, it has been suggested that the pathophysiology of migraine is likely to involve glutamate, the main excitatory neurotransmitter in the central nervous system (CNS). Glutamate plays a role in nociception, central sensitization, and cortical spreading depression (CSD), three processes that are deemed important in migraine biology. With an emphasis on the therapeutic potential of targeting various glutamate receptors in migraine, this review will discuss the currently available literature and emerging findings on the role of targeting glutamatergic pathways for the treatment of migraine. A thorough literature review was carried out on the functions of both metabotropic glutamate receptors (mGluRs), and the ionotropic glutamate receptors (NMDA, AMPA, and kainate) in migraine pathogenesis. The ever-present need for new treatments, the role of glutamate in the migraine aura phenomenon, and the consequences of monogenic migraine mutations on mediating prolonged, complex, or permanent aura are all discussed, culminating in a suggestion that glutamatergic targeting may hold particular promise in the management of migraine aura. There are plausible roles for metabotropic receptors in regulating pain processing in important migraine-related brain structures, like the thalamus and trigeminal nucleus. Similarly, ionotropic receptors contribute to excitatory neurotransmission and neuronal hyperexcitability. Recent studies have shown preclinical and early clinical results for treatments targeting these receptors, but there are still significant issues with treatment response, including drug transport, side effects, and efficacy. With ongoing and emerging discoveries in the field, there is increasing promise of new migraine medications targeting glutamate receptors. For bench to bedside translation in this area, continued study of the molecular basis of migraine, receptor subtypes, and exploration of potential drug delivery methods are needed. Full article

Prenatal hyperhomocysteinemia (HCY) is associated with neurodevelopmental deficits, yet its long-term impact on hippocampal synaptic function remains poorly understood. This study examines the effects of moderate maternal HCY on excitatory synaptic transmission in the CA1 region of the dorsal hippocampus in rat offspring at juvenile (P21) and adult (P90) stages. Using field postsynaptic potential (fPSP) recordings, electron microscopy, and Western blot analysis, we observed a significant age-dependent decline in the efficiency of excitatory synaptic transmission in HCY-exposed rats. Electron microscopy revealed structural alterations, including synaptic vesicle agglutination in the stratum radiatum, suggesting impaired neurotransmitter release. Additionally, a significant reduction in pyramidal neuron density was observed in the CA1 region, although seizure susceptibility remained unchanged. Western blot analysis showed altered expression of Synapsin I, indicating presynaptic dysfunction. These findings suggest that moderate prenatal HCY leads to persistent deficits in synaptic transmission and structural integrity, potentially contributing to cognitive impairments in adulthood. Our results highlight the importance of maternal homocysteine levels in shaping hippocampal function and could offer insights into neurodevelopmental disorders associated with metabolic disturbances. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, with women being disproportionately affected in both prevalence and severity. A key feature of AD is synaptic loss, particularly around amyloid-β (Aβ) aggregates, which correlates strongly with the severity of dementia. Oligomeric Aβ is believed to be the primary driver of synaptic dysfunction by impairing excitatory neurotransmission through interactions with synaptic receptors, including N-methyl-D-aspartate (NMDA) receptors. However, the influence of sex on these synaptic changes and NMDA receptor mislocalization in AD is not well understood. This study examined potential sex-specific differences in synaptotoxicity and the role of extrasynaptic GluN2B-containing NMDA receptors in AD pathogenesis using the APP/PS1 double transgenic mouse model. Although both male and female mice showed a similar amyloid burden and cognitive impairments, synaptic alterations were slightly less severe in females, suggesting subtle sex differences in synaptic pathology. Both sexes exhibited the mislocalization of GluN2B subunits to extrasynaptic areas, which was linked to reduced PSD-95 levels and the synaptic accumulation of Aβ_1–42. Intrahippocampal injections of DL-TBOA confirmed the role of extrasynaptic GluN2B-containing NMDA receptors in memory dysfunction. These findings emphasize the importance of targeting synaptic receptor trafficking to address AD-related memory deficits, potentially offering a therapeutic approach for both sexes. Full article

Epilepsy is a chronic neurological disorder marked by recurrent seizures, significantly impacting individuals worldwide. Current treatments are often ineffective for a third of patients and can cause severe side effects, necessitating new therapeutic approaches. Glial cells, particularly astrocytes, microglia, and oligodendrocytes, are emerging as crucial targets in epilepsy management. Astrocytes regulate neuronal homeostasis, excitability, and synaptic plasticity, playing key roles in maintaining the blood–brain barrier (BBB) and mediating neuroinflammatory responses. Dysregulated astrocyte functions, such as reactive astrogliosis, can lead to abnormal neuronal activity and seizure generation. They release gliotransmitters, cytokines, and chemokines that may exacerbate or mitigate seizures. Microglia, the innate immune cells of the CNS, contribute to neuroinflammation, glutamate excitotoxicity, and the balance between excitatory and inhibitory neurotransmission, underscoring their dual role in seizure promotion and protection. Meanwhile, oligodendrocytes, primarily involved in myelination, also modulate axonal excitability and contribute to the neuron–glia network underlying seizure pathogenesis. Understanding the dynamic interactions of glial cells with neurons provides promising avenues for novel epilepsy therapies. Targeting these cells may lead to improved seizure control and better clinical outcomes, offering hope for patients with refractory epilepsy. Full article

Background/Objectives: Tinnitus is a debilitating auditory disorder commonly described as a ringing in the ears in the absence of an external sound source. Sound trauma is considered a primary cause. Neuronal hyperactivity is one potential mechanism for the genesis of tinnitus and has been identified in the cochlear nucleus (CN) and the auditory cortex (AC), where there may be an imbalance of excitatory and inhibitory neurotransmissions. However, no study has directly correlated tinnitus with the extracellular levels of amino acids in the CN and the AC using microdialysis, which reflects the functions of these neurochemicals. In the present study, rats were exposed to acoustic trauma and then subjected to behavioural confirmation of tinnitus after one month, followed by microdialysis. Methods: Rats were divided into sham (aged, n = 6; young, n = 6); tinnitus-positive (aged, n = 7; young, n = 7); and tinnitus-negative (aged, n = 3; young, n = 3) groups. In vivo microdialysis was utilized to collect samples from the CN and the AC, simultaneously, in the same rat. Extracellular levels of amino acids were quantified using high-performance liquid chromatography (HPLC) coupled with an electrochemical detector (ECD). The effects of sound stimulation and age on neurochemical changes associated with tinnitus were also examined. Results: There were no significant differences in either the basal levels or the sound stimulation-evoked changes of any of the amino acids examined in the CN and the AC between the sham and tinnitus animals. However, the basal levels of serine and threonine exhibited age-related alterations in the AC, and significant differences in threonine and glycine levels were observed in the responses to 4 kHz and 16 kHz stimuli in the CN. Conclusions: These results demonstrate the lack of a direct link between extracellular levels of amino acids in the CN and the AC and tinnitus perception in a rat model of tinnitus. Full article

Neurodevelopmental disorders (NDDs) are a group of conditions affecting brain development, with variable degrees of severity and heterogeneous clinical features. They include intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), often coexisting with epilepsy, extra-neurological comorbidities, and multisystemic involvement. In recent years, next-generation sequencing (NGS) technologies allowed the identification of several gene pathogenic variants etiologically related to these disorders in a large cohort of affected children. These genes encode proteins involved in synaptic homeostasis, such as SNARE proteins, implicated in calcium-triggered pre-synaptic release of neurotransmitters, or channel subunit proteins, such as post-synaptic ionotropic glutamate receptors involved in the brain’s fast excitatory neurotransmission. In this narrative review, we dissected emerged molecular mechanisms related to NDDs and epilepsy due to defects in pre- and post-synaptic transmission. We focused on the most recently discovered SNAREopathies and AMPA-related synaptopathies. Full article

The mechanisms of epileptogenesis after brain injury, ischemic stroke, or brain tumors have been extensively studied. As a result, many effective antiseizure drugs have been developed. However, there are still many patients who are resistant to therapy. The molecular and genetic bases regarding such drug-resistant seizures have been poorly elucidated. In many cases, heavy seizures are instigated by brain development malformations and often caused by gene mutations. Such malformations can be demonstrated in mouse models by generating mutant strains. One of the most potent mutagens is ENU (N-ethyl-N-nitrosourea). In the present study, we describe three novel mutant strains generated by ENU-directed mutagenesis. Two of these strains present a very strong epileptic phenotype triggered by audiogenic stimuli (G9-1 and S5-1 strains). The third mouse strain is characterized by behavioral disorders and hyperexcitation of neuronal networks. We identified changes in the expression of those genes encoding neurotransmission proteins in the cerebral cortexes of these mice. It turned out that the G9-1 strain demonstrated the strongest disruptions in the expression of those genes encoding plasma membrane channels, excitatory glutamate receptors, and protein kinases. On the other hand, the number of GABAergic neurons was also affected by the mutation. All three lines are characterized by increased anxiety, excitability, and suppressed motor and orientational–exploratory activities. On the other hand, the strains with an epileptic phenotype—G9-1 and S5-1ave reduced learning ability, and the A9-2 mice line retains high learning ability. Full article

Functional gastrointestinal disorders (FGIDs) are characterized by chronic gastrointestinal symptoms in the absence of overt pathology and affect a significant percentage of the worldwide population. They are commonly accompanied by co-morbid psychiatric symptomatology and are associated with significant suffering and great healthcare services utilization. There is growing evidence that dysregulation of the gut–brain axis and disturbances in the processing of afferent interoceptive signals lie at the heart of these disorders. In this context, the aim of the current review was to detect and critically review original articles focusing on the role of interoception in the pathophysiology of FGIDs. Our search yielded 38 relevant studies. FGID patients displayed increased visceral sensitivity, enhanced attention to gastrointestinal interoceptive cues, and greater emotional arousal when coping with gut-derived sensations. Neuroimaging studies have shown significant structural and functional changes in regions of the interoceptive network, while molecular and genetic studies have revealed significant associations between interoceptive signaling and deficits in excitatory neurotransmission, altered endocrine and immune physiological pathways, and aberrant expression of transient receptor potential channel genes. Finally, there were emerging data suggesting that interoception-based interventions may reduce physical symptoms and improve quality of life and should be integrated into FGID clinical management practices. Full article

Glycine plays a pivotal role in the Central Nervous System (CNS), being a major inhibitory neurotransmitter as well as a co-agonist of Glutamate at excitatory NMDA receptors. Interactions involving Glycine and other neurotransmitters are the subject of different studies. Functional interactions among neurotransmitters include the modulation of release through release-regulating receptors but also through transporter-mediated mechanisms. Many transporter-mediated interactions involve the amino acid transmitters Glycine, Glutamate, and GABA. Different studies published during the last two decades investigated a number of transporter-mediated interactions in depth involving amino acid transmitters at the nerve terminal level in different CNS areas, providing details of mechanisms involved and suggesting pathophysiological significances. Here, this evidence is reviewed also considering additional recent information available in the literature, with a special (but not exclusive) focus on glycinergic neurotransmission and Glycine–Glutamate interactions. Some possible pharmacological implications, although partly speculative, are also discussed. Dysregulations in glycinergic and glutamatergic transmission are involved in relevant CNS pathologies. Pharmacological interventions on glycinergic targets (including receptors and transporters) are under study to develop novel therapies against serious CNS pathological states including pain, schizophrenia, epilepsy, and neurodegenerative diseases. Although with limitations, it is hoped to possibly contribute to a better understanding of the complex interactions between glycine-mediated neurotransmission and other major amino acid transmitters, also in view of the current interest in potential drugs acting on “glycinergic” targets. Full article

An optimal balance between excitatory and inhibitory transmission in the central nervous system provides essential neurotransmission for good functioning of the neurons. In the neurology field, a disturbed balance can lead to neurological diseases like epilepsy, Alzheimer’s, and Autism. One of the critical agents mediating excitatory neurotransmission is α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors, which are concerned with synaptic plasticity, memory, and learning. An imbalance in neurotransmission finally results in excitotoxicity and neurological pathologies that should be corrected through specific compounds. Hence, the current study will prove to be an evaluation of new thiazole-carboxamide derivatives concerning AMPAR-modulating activity and extended medicinal potential. In the current project, five previously synthesized thiazole-carboxamide derivatives, i.e., TC-1 to TC-5, were used to interact with the AMPARs expressed in HEK293T cells, which overexpress different subunits of the AMPAR. Patch-clamp analysis was carried out while the effect of the drugs on AMPAR-mediated currents was followed with a particular emphasis on the kinetics of inhibition, desensitization, and deactivation. All tested TC compounds, at all subunits, showed potent inhibition of AMPAR-mediated currents, with TC-2 being the most powerful for all subunits. These compounds shifted the receptor kinetics efficiently, mainly enhancing the deactivation rates, and hence acted as a surrogate for their neuroprotective potentials. Additionally, recently published structure–activity relationship studies identified particular substituent groups as necessary for improving the pharmacologic profiles of these compounds. In this regard, thiazole-carboxamide derivatives, particularly those classified as TC-2, have become essential negative allosteric modulators of AMPAR function and potential therapeutics in neurological disturbances underlain by the dysregulation of excitatory neurotransmission. Given their therapeutic effectiveness and safety profiles, these in vivo studies need to be further validated, although computational modeling can be further developed for drug design and selectivity. This will open possibilities for new drug-like AMPAR negative allosteric modulators with applications at the clinical level toward neurology. Full article

Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS), plays a pivotal role in maintaining the delicate balance between inhibitory and excitatory neurotransmission. Dysregulation of the excitatory/inhibitory balance is implicated in various neurological and psychiatric disorders, emphasizing the critical role of GABA in disease-free brain function. The review examines the intricate interplay between the gut–brain axis and CNS function. The potential impact of dietary GABA on the brain, either by traversing the blood–brain barrier (BBB) or indirectly through the gut–brain axis, is explored. While traditional beliefs questioned GABA’s ability to cross the BBB, recent research challenges this notion, proposing specific transporter systems facilitating GABA passage. Animal studies provide some evidence that small amounts of GABA can cross the BBB but there is a lack of human data to support the role of transporter-mediated GABA entry into the brain. This review also explores GABA-containing food supplements, investigating their impact on brain activity and functions. The potential benefits of GABA supplementation on pain management and sleep quality are highlighted, supported by alterations in electroencephalography (EEG) brain responses following oral GABA intake. The comprehensive overview encompasses GABA’s sources in the diet, including brown rice, soy, adzuki beans, and fermented foods. GABA’s presence in various foods and supplements, its association with gut microbiota, and its potential as a therapeutic strategy for neurological disorders are thoroughly examined. The articles were retrieved through a systematic review of the databases: OVID, SCOPUS, and PubMed (keywords “GABA”, “oral GABA“, “sleep”, “cognition”, “neurodegenerative”, “blood-brain barrier”, “gut microbiota”, “supplements” and “therapeutic”, and by searching reference sections from identified studies and review articles). This review presents the relevant literature available on the topic and discusses the mechanisms, effects, and hypotheses that suggest oral GABA benefits range from neuroprotection to blood pressure control. The literature suggests that oral intake of GABA affects the brain illustrated by changes in EEG scans and cognitive performance, with evidence showing that GABA can have beneficial effects for multiple age groups and conditions. The potential clinical and research implications of utilizing GABA supplementation are vast, spanning a spectrum of diseases ranging from neurodegeneration to blood pressure regulation. Importantly, recommendations for the use of oral GABA should consider the dosage, formulation, and duration of treatment as well as potential side effects. Effects of GABA need to be more thoroughly investigated in robust clinical trials to validate efficacy to progress the development of alternative treatments for a variety of disorders. Full article