Search Results (735)

Fast-channel genetic myasthenic syndromes (FCGMSs) are caused by genetic variants in muscle nicotinic acetylcholine receptor (AChR) subunits that reduce channel open times and impair neuromuscular transmission. Among these, the CHRNE p.P141L variant (εP141L) is associated with particularly severe disease. Here, we characterized a knock-in mouse model harboring the homologous p.P141L variant in Chrne (εP141L)—C57BL/6J-Chrne^em1H/H made by the MRC GEMM program. Homozygous mutant mice fail to thrive, with early lethality (median survival of 16 days), closely recapitulating the severity observed in patients. Despite a preserved neuromuscular junction (NMJ) morphology and robust AChR expression, electrophysiological analyses revealed marked reductions in miniature and evoked endplate potential amplitudes and areas, accompanied by prolonged depolarization kinetics (contrary to expectations for AChR with reduced open times) and increased quantal content, indicative of impaired post-synaptic function with compensatory pre-synaptic adaptation. Notably, disease severity exceeded that of Chrne null mice, likely through competition with more functional g-subunit-containing fetal AChRs. Consistent with this, crossing εP141L mice with CHRNG-expressing mice provided little survival benefit. These findings demonstrate that dysfunctional AChR incorporation is more deleterious than receptor absence and highlight the critical role of subunit composition in sustaining neuromuscular transmission. Pharmacological enhancement of pre-synaptic release with 3,4-diaminopyridine partially improved synaptic parameters. In addition, the AChR-positive allosteric modulator DC-98 modestly improved neurotransmission. Thus, this mouse model provides a faithful platform for mechanistic studies and therapeutic development in FCGMS. Full article

Motoneurons are under strong pressure to maintain stable motor output throughout an individual life, through homeostatic regulation of their electrical properties. Dysregulated spinal motoneuron excitability has long been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Recent work in SOD1^G93A mice suggests that the homeostatic response of motoneurons becomes dysregulated as cellular processes are disrupted by the disease, causing fluctuations in motoneuron electrical properties. Yet, few studies directly test whether ALS motoneurons respond differently than wild-type motoneurons to a common chronic perturbation. Here, we used in vivo electrophysiology to test whether motoneurons from pre-symptomatic SOD1^G93A mice modulate excitability differently than wild-type motoneurons in response to the same homeostatic perturbation: chronic inhibition exerted by the benzodiazepine diazepam. Using linear mixed-effects statistical models, we assessed whether diazepam treatment differentially modulated passive properties, firing behavior, spike properties, and/or synaptic inputs in SOD1^G93A versus wild-type motoneurons. We identified a significant genotype × treatment interaction effect selectively for properties related to passive membrane integration and spike initiation, including membrane time constant, peak input resistance, and recruitment current. In contrast, firing gain, spike waveform characteristics, and synaptic inputs were largely unaffected. These findings indicate that sustained inhibitory perturbation selectively triggered overactive intrinsic compensatory mechanisms in SOD1^G93A motoneurons rather than inducing widespread changes in firing or synaptic transmission. Together, our results provide direct evidence for over-active homeostatic control of motoneuron excitability and support a view of motoneuron dysfunction in ALS as a problem of altered feedback regulation rather than simply hyper- or hypo-excitability. Full article

Common forms of migraine are complex disorders characterized by significant clinical diversity. Their genetic basis has been extensively studied but remains unclear. This study represents the first pilot genome-wide association study (GWAS) integrating a polygenic risk score (PRS) in the Portuguese population, designed to identify migraine susceptibility loci through a case–control study and unravel population-specific variants. Genotyping data was acquired with Applied Biosystems Axiom™ PMDA array, producing 12,035,248 single-nucleotide polymorphisms (SNPs) post-imputation, providing a comprehensive scope for GWAS analysis. PRS models were created and tested using a k-folds cross-validation framework and the optimal significance threshold was assessed. We detected 12 potential risk loci corresponding to 12 lead SNPs (RP11-204N11.2, CTA-481E9.4/CTA-481E9.3, RAP1A, TIGD4, CADPS2, RP11-46E17.6, RP4-569D19.5, RP11-398K14.1, PCBP1-AS1, TCF15, IL6R and UNC13A). The top three variants (RP11-204N11.2, CTA-481E9.4/CTA-481E9.3 and RAP1A) were also supported by the PRS model. We highlight that several variants present putative biological relevance to migraine pathophysiology, reinforcing the importance of neurotransmitter release, synaptic transmission and the involvement of vascular components in migraine pathophysiology. Full article

The mechanism of action of mice in chronic stress-induced depressive like behavior remains unclear. In this study, we found that chronic social defeat stress (CSDS) upregulates Drp1 expression in mouse hippocampal tissue, leading to excessive mitochondrial fission, which further impairs bioenergetics, induces oxidative stress, disrupts mitochondrial autophagy, and reduces excitatory synaptic transmission. Stereotactic injection of Drp1 inhibitor Mdivi-1 into the hippocampus reversed the aforementioned neuronal defects and alleviated CSDS-induced depressive-like behaviors, including social avoidance, anhedonia, and behavioral despair. Our findings indicate that elevated Drp1 triggers mitochondrial fission, representing a key pathophysiological mechanism underlying stress-induced depression. Therefore, targeting the regulation of mitochondrial dynamics may represent a viable therapeutic strategy. Full article

Self-limited focal epilepsies in childhood (SELFEs), formerly referred to as “benign epilepsies in childhood”, constitute a heterogeneous group of epileptic conditions with onset predominantly in the neonatal, infantile, and childhood periods. A defining feature of these syndromes is that seizures arise without underlying structural, metabolic, or other demonstrable cerebral pathology, and the overall clinical trajectory is expected to be favorable, with seizures resolving spontaneously over time. Current nosological frameworks divide SELFEs into two broad categories according to age at onset: (a) neonatal and infantile forms, encompassing self-limited familial and non-familial neonatal, neonatal-infantile, and infantile epilepsies, genetic epilepsy with febrile seizures plus (GEFS+), and myoclonic epilepsy of infancy (MEI); and (b) childhood-onset forms, including self-limited epilepsy with centrotemporal spikes (SeLECTS), self-limited epilepsy with autonomic seizures (SeLEAS), childhood occipital visual epilepsy (COVE), and photosensitive occipital lobe epilepsy (POLE). Despite their historically “benign” label, there is no general agreement to include GEFS + and MEI among the group of SELFEs as both these conditions have been not classified as focal epilepsy in general. Accumulating evidence shows that a subset of affected children subsequently develop additional seizure types, cognitive deterioration, and behavioral or neuropsychiatric difficulties—outcomes that the word “benign” does not adequately communicate. Advances in molecular genetics have identified pathogenic variants affecting ion channels, synaptic transmission, and neuronal excitability, reshaping current understanding of disease mechanisms and phenotypic variability across these syndromes. This review highlights clinically relevant challenges in the diagnosis and management of SELFEs, critically examines emerging genotype–phenotype correlations, and provides evidence-based recommendations for antiseizure medication initiation and withdrawal tailored to individual syndrome characteristics and risk profiles. Full article

Background/Objectives: Chronic urate nephropathy (CUN), also referred to as gouty nephropathy, represents a severe renal disease primarily precipitated by long-term hyperuricemia (HUA) and gout. However, the precise molecular mechanisms underlying its pathogenesis remain poorly understood. The present study was designed to explore these mechanisms from the perspective of targeted metabolomics. Methods: The HUA mice constructed by urate oxidase (Uox) gene knockout (KO) and their corresponding wild-type controls were employed for the present study. Serum clinical biochemical parameters were determined, and renal histopathological changes were evaluated using hematoxylin-eosin (HE) staining and Masson’s trichrome staining. A targeted metabolomic strategy based on multiple reaction monitoring (MRM) was utilized to profile the renal metabolic landscape of Uox-KO mice, and potential metabolic biomarkers for CUN were identified via multivariate data analysis. Results: Clinical biochemical analysis revealed a significant elevation in serum uric acid, creatinine, and urea nitrogen levels in Uox-KO mice compared with control mice. Histopathological observations confirmed a typical CUN phenotype in Uox-KO mice, characterized by renal tubular vacuolar degeneration and dilatation, desquamation of tubular epithelial cells into the lumen, neutrophil infiltration, glomerular crowding, and renal interstitial fibrosis. Metabolomic analysis identified a total of 291 differentially regulated metabolites in Uox-KO mice relative to control animals. These perturbed metabolites were involved in multiple key biochemical pathways, including amino acid biosynthesis, ABC transporter signaling pathway, purine metabolism, aminoacyl-tRNA biosynthesis, protein digestion and absorption, glycerophospholipid metabolism, and serotonergic synaptic transmission. Notably, pathological parameters, including biochemical measurements and histological observations, were significantly correlated with key differential metabolites associated with CUN progression. Furthermore, eleven differential metabolites (pyroglutamic acid, fructose, riboflavin, dimethyl-L-arginine, glucaric acid, indoxyl sulfate, palmitoylethanolamide, trimethylamine N-oxide, 3-hydroxyanthranilic acid, spermidine, and hippuric acid) were identified as potential metabolic biomarkers for the diagnosis and prognosis of CUN. Conclusions: These findings illustrate that targeted tissue metabolomic analysis constitutes a powerful tool for deciphering the molecular mechanisms of diseases, thus offering novel insights into the pathogenesis of CUN. Full article

Pregabalin (PGB) exerts its therapeutic effects by binding to the α₂δ auxiliary subunits of voltage-gated calcium channels and modulates synaptic transmission in the brain. However, its influence on cerebellar parallel fiber–Purkinje cell (PF–PC) synaptic transmission remains unclear. In the present study, we investigated the effects of PGB on PF–PC synaptic transmission using whole-cell patch-clamp recording, glutamate fluorescence imaging, immunohistochemistry, co-immunoprecipitation, Western blotting, and pharmacological approaches. Micro-application of PGB to the cerebellar molecular layer induced a concentration-dependent inhibition of PF–PC excitatory postsynaptic currents (EPSCs), accompanied by an increased paired-pulse ratio. The inhibitory effect of PGB on PF–PC EPSCs was abolished by extracellular blockade of N-methyl-D-aspartate receptors (NMDAR) or their GluN2A subtype, as well as by disruption of α₂δ-1–NMDAR complexes, but not by intracellular NMDAR inhibition. Glutamate sensor imaging further showed that PGB markedly reduced the fluorescence intensity of glutamate release evoked by PF stimulation. In the presence of tetrodotoxin (TTX) and a gamma-aminobutyric acid type A (GABAA) receptor antagonist, PGB reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) without affecting their amplitude. The PGB-induced reduction in mEPSC frequency was fully abolished by extracellular blockade of GluN2A-containing NMDARs or disruption of α₂δ-1–NMDAR complexes. Similarly, the inhibitory effects of PGB on PF–PC EPSCs and mEPSCs were eliminated by extracellular PKA inhibition, but not by intracellular protein kinase A (PKA) inhibition. Western blot analysis showed that PGB significantly increased PKA phosphorylation in the molecular layer of the cerebellar cortex. Immunoreactivity for GluN2A and α₂δ-1 subunits was colocalized within the molecular layer and abundantly distributed around the dendrites and somata of PCs. Co-immunoprecipitation further verified that α₂δ-1 was co-precipitated with GluN1 in cerebellar molecular layer tissue samples. The results indicate that PGB depresses glutamate release from parallel-fiber terminals in the mouse cerebellar cortex through the presynaptic α₂δ-1-coupled GluN2A-containing NMDAR/PKA signaling pathway, thereby attenuating PF–PC synaptic transmission. Full article

Background/Objectives: Increasing evidence indicates that gliomas co-opt mechanisms of excitatory synaptic transmission and plasticity to support tumor progression, yet these processes remain poorly characterized in lower-grade gliomas (LGGs). Here, we investigated whether genes associated with excitatory synaptic function are linked to patient prognosis in LGG. Methods: A curated panel of 36 synaptic genes was analyzed in LGG using RNA-sequencing and clinical data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Results: Among the genes investigated, DLG2, DLG3, and DLG4, which encode the postsynaptic scaffolding proteins PSD-93, SAP-102, and PSD-95, respectively, showed strong associations with patient overall survival (OS). Higher expression of each gene was consistently associated with longer OS across both datasets. Expression of DLG2–DLG4 was higher in oligodendroglioma and IDH-mutant, 1p/19q co-deleted tumors, and lower in astrocytoma and IDH-wild-type tumors. Furthermore, expression of all three genes positively correlated with a broad gene signature associated with a synaptic gene program, including multiple components of glutamatergic signaling and postsynaptic organization. Conclusions: These findings suggest that elevated expression of DLG2–DLG4 is associated with a transcriptional program resembling differentiated neuron-like features and favorable clinical outcome in LGG. Full article

Mitochondrial dysfunction is a key contributor to cognitive impairment, directly affecting neuronal viability, synaptic function, and energy metabolism. In the central nervous system, where energy demand is particularly high, disturbances in mitochondrial dynamics, including impaired oxidative phosphorylation (OxPhos), increased reactive oxygen species (ROS) production, and reduced ATP availability, can compromise synaptic transmission and accelerate cognitive decline. These alterations are commonly observed in neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD), in which mitochondrial dysfunction is closely associated with oxidative stress and neuroinflammatory processes. This review aims to investigate the role of mitochondrial dysfunction in cognitive impairment and the effects of physical exercise as a non-pharmacological strategy to mitigate these alterations. Current evidence indicates that exercise promotes mitochondrial biogenesis through activation of the AMPK/PGC-1α pathway, enhances oxidative metabolism, and improves mitochondrial efficiency. Furthermore, exercise reduces oxidative stress and inflammation while stimulating the release of neurotrophic factors, such as brain-derived neurotrophic factor which support neurogenesis, synaptic plasticity, and neuronal survival. Overall, these findings reinforce the importance of mitochondrial integrity in maintaining cognitive function and highlight physical exercise as a promising strategy to counteract mitochondrial dysfunction and delay the progression of neurodegenerative diseases. Full article

Background/Objectives: Brain tumors, particularly gliomas, have high mortality and are limited in treatment options, often complicated by severe conditions, which can be fatal. Given the increasing incidence and adverse effects of current drugs, an in silico drug repurposing approach using hub gene clusters to streamline and accelerate the search for new therapies. Methods: The GSE66354, GSE68848, GSE74195, and GSE43290 datasets were used to identify DEGs using GEO2R. A gene co-expression network was constructed using the STRING PPI database. Preserved clusters revealed hub genes, which were used for GO and KEGG pathway enrichment analyses. Drug repurposing screening was performed through drug–gene interactions in DGIdb. Suggestive drugs were then validated through GSEA-CMAP and BOILED-Egg. Results: The study identified three key gene clusters that serve a role in synaptic transmission and transmembrane transport, synaptic vesicle neurotransmission, and extracellular matrix formation. Five drugs passed the drug screening, which are Gabapentin, Pyrantel, Resveratrol, Trifluoperazine, and Valproic acid. Conclusions: Valproic acid and Gabapentin are highly suggestive as candidate repurposed drugs. This study enhances our understanding of brain tumor genetics and supports the development of new immunotherapeutic strategies. Full article

Acetylcholine (ACh) is the first identified neurotransmitter and an evolutionarily conserved signaling molecule. Although its role in classical synaptic transmission within the central and peripheral nervous systems has been extensively studied, growing evidence indicates that cholinergic signaling extends beyond neuronal synapses and operates in a broad range of non-neuronal cells. Thus, the cholinergic system represents a complex and widely distributed signaling network with both neuronal and non-neuronal components. Within the nervous system, cholinergic neurons display marked molecular heterogeneity, largely driven by the genomic organization and alternative splicing of the choline acetyltransferase (ChAT) gene. Distinct ChAT mRNA splice variants contribute to region- and cell-type specific cholinergic phenotypes in central and peripheral neurons, including the enteric nervous system, which exemplifies a highly autonomous peripheral cholinergic network. Beyond the nervous system, non-neuronal cholinergic signaling has been identified in epithelial, cardiac, immune, and other cell types, where ACh acts as an autocrine and paracrine regulator of key physiological processes. This review summarizes current knowledge on ACh biosynthesis, focusing on ChAT and its splice variants as molecular determinants of cholinergic diversity and function across neuronal and non-neuronal contexts. Full article

Chronic pain, a complex multidimensional disorder, remains a major healthcare issue and a therapeutic challenge. Neuropathic pain is a chronic pain condition that results from damage or dysfunction in the nervous system. While mechanisms of neuropathic pain at the peripheral and spinal cord level have been extensively studied, pain mechanisms in the brain remain underexplored. The amygdala, a limbic brain region, has emerged as a critical brain area for the emotional–affective dimension of pain and pain modulation. Amygdala neuroplasticity has been associated with pain states, but the exact molecular and cellular mechanisms underlying these states and the transition from acute to chronic pain are not well understood. Here, we used the spinal nerve ligation (SNL) model of neuropathic pain in male rats to investigate changes in gene expression in the amygdala at the chronic pain stage using RNA sequencing (RNA-Seq). Two amygdala nuclei, the basolateral (BLA) and central (CeA), were investigated in a hemisphere-dependent manner. We used an integrative approach that focuses on functional significance and cell-type specificity of differentially expressed genes (DEGs) to nominate mechanistic targets for central regulation of chronic pain. Our integrative transcriptomic and bioinformatic analyses identified individual genes (e.g., Cxcl10, Cxcl12, Mbp, Plp1, Mag, Mog, Slc17a6, Gad1, and Sst), molecular pathways (e.g., cytokine-mediated signaling pathway), biological processes (e.g., myelination, synaptic transmission), and specific cell types (e.g., oligodendrocytes, glutamatergic, and GABAergic neurons) affected by chronic pain. Our results also provide some evidence for the emerging concept of hemispheric lateralization of pain processing in the amygdala. Overall, our study proposes oligodendrocyte dysfunction in the amygdala, neuroimmune signaling in the CeA, and glutamatergic neurotransmission in the BLA as key processes and potential therapeutic targets for the management of chronic neuropathic pain. Full article

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance. Full article

Opioid analgesics are essential in the management of severe and chronic pain; however, their prolonged use is limited by the onset of analgesic tolerance and opioid-induced hyperalgesia (OIH). Recent studies increasingly implicate both synaptic functional and structural plasticity within nociceptive pathways as crucial mechanisms in OIH and tolerance. This review integrates current mechanistic understanding of how opioids alter synaptic transmission throughout the dorsal root ganglia (DRG), spinal dorsal horn, and supraspinal nociceptive networks. Peripherally, μ-opioid receptor (MOR) activation on TRPV1-positive nociceptors initiates presynaptic long-term potentiation (LTP), forming an early substrate for central sensitization. In the spinal dorsal horn, chronic opioid exposure drives NMDAR-dependent LTP, TRPC-mediated calcium influx, and actin cytoskeleton remodeling, leading to persistent increases in synaptic strength and excitatory connectivity. In supraspinal regions—including the ventral hippocampus, prefrontal cortex, and amygdala—opioids promote experience-dependent plasticity and predictive coding, which link environmental cues to reduced analgesic effectiveness. In addition to synaptic functional plasticity, opioid-induced synaptic structural plasticity within nociceptive pathways has been shown to underlie the long-term nature of opioid analgesic tolerance. Collectively, these data define a distributed network of opioid-responsive synapses whose pathological potentiation underpins the development of tolerance and hyperalgesia. Elucidating these mechanisms underlying OIH and tolerance paves the way for targeted therapeutic strategies that maintain analgesic efficacy while minimizing adverse synaptic remodeling and negative outcomes. Full article

Aging is characterized by progressive degeneration of neuromuscular junctions (NMJs), which significantly contributes to muscle weakness and the development of sarcopenia. Photobiomodulation (PBM), a non-invasive therapeutic method based on the use of low-intensity light, has shown promising results in mitigating muscle degeneration in both experimental and clinical studies. The aim of this study was to evaluate the ultrastructural effects of photobiomodulation on neuromuscular junctions and skeletal muscle fibers in the m. vastus lateralis muscle of aged rats using light and transmission electron microscopy. Male Wistar rats (18 months old, body weight 650–800 g, n = 10) were subjected to photobiomodulation of the right m. vastus lateralis muscle (650 nm, 6 J/cm², four consecutive daily sessions of 3 min each). The contralateral left limb served as an untreated control. Muscle samples were analyzed by light and transmission electron microscopy. Histological examination revealed typical age-related changes in control muscles, including variability in muscle fiber diameter, centrally located nuclei, and an increased volume of connective tissue. Ultrastructural analysis confirmed signs of skeletal muscle aging, such as myofibril fragmentation, sarcomere disorganization, lipofuscin accumulation, and tubular aggregate formation. Morphometric analysis of neuromuscular junctions after photobiomodulation showed an increase in the number of active zones on the presynaptic membrane, elongation of the postsynaptic membrane, and a reduction in the width of the synaptic cleft. In addition, mitochondrial hyperplasia was observed in presynaptic terminals, while the total number of synaptic vesicles decreased. These findings indicate a compensatory reorganization of neuromuscular junctions and suggest that photobiomodulation can enhance their functional activity in aged skeletal muscle. Full article