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PubMed2024

Advances in serum thyroid hormone levels and seizures.

Epilepsy, a common neurological disorder, is characterized by paroxysmal, short-term, repetitive, and stereotypical features, significantly impacting patients' quality of life. Currently, the pathogenesis of epilepsy remains incompletely understood. Changes in neuronal excitability, imbalances in glutamate and gamma-aminobutyric acid (GABA) levels, alterations in the activity of GABA receptors, and dysfunction of GABA receptors are considered closely related to its occurrence. Thyroid hormones, vital for human growth and development, also play a crucial role in the nervous system. They mediate oxidative stress, influence reactive oxygen species production, affect mitochondrial function and neuronal excitability, and modulate glutamate and GABA levels. Also, they combine with thyroid hormone receptors and exert genomic effects by regulating the expression of numerous genes. However, once there are defects in thyroid hormone signaling, these defects may lead to severe neurodevelopmental disorders that are associated with an increased frequency of seizures. The impact of antiseizure medications (ASMs) on serum thyroid hormone levels, particularly traditional ASMs, has been extensively studied. It is reported that conventional ASMs such as phenobarbital, phenytoin sodium, carbamazepine, and valproate sodium were more likely to induce subclinical hypothyroidism (elevated TSH with normal FT4) or isolated hypothyroidism (decreased FT4 with normal TSH). However, the new ASMs, such as levetiracetam, have no effect on thyroid hormone levels. Together, seizures not only affect thyroid hormone levels, but abnormal thyroid hormone levels can also influence seizures. However, the precise mechanism underlying the interaction between serum thyroid hormone levels and seizures remains unclear. This review aims to explore the relationship between thyroid hormone levels and seizures, along with the underlying mechanisms.

Humans↗

PubMed2025

Chaperone-mediated autophagy regulates neuronal activity by sex-specific remodelling of the synaptic proteome.

Chaperone-mediated autophagy (CMA) declines in ageing and neurodegenerative diseases. Loss of CMA in neurons leads to neurodegeneration and behavioural changes in mice but the role of CMA in neuronal physiology is largely unknown. Here we show that CMA deficiency causes neuronal hyperactivity, increased seizure susceptibility and disrupted calcium homeostasis. Pre-synaptic neurotransmitter release and NMDA receptor-mediated transmission were enhanced in CMA-deficient females, whereas males exhibited elevated post-synaptic AMPA-receptor activity. Comparative quantitative proteomics revealed sexual dimorphism in the synaptic proteins degraded by CMA, with preferential remodelling of the pre-synaptic proteome in females and the post-synaptic proteome in males. We demonstrate that genetic or pharmacological CMA activation in old mice and an Alzheimer's disease mouse model restores synaptic protein levels, reduces neuronal hyperexcitability and seizure susceptibility, and normalizes neurotransmission. Our findings unveil a role for CMA in regulating neuronal excitability and highlight this pathway as a potential target for mitigating age-related neuronal decline.

Animals↗

PubMed2026

A massively parallel CRISPR-based screening platform for modifiers of neuronal depolarization.

Understanding the complex interplay between gene expression and neuronal activity is crucial for unraveling the molecular mechanisms underlying cognitive function and neurological disorders. Here, we developed pooled screens using CRISPR interference (CRISPRi) and the fluorescent calcium integrator CaMPARI2 to evaluate genetic modifiers of neuronal depolarization. Using this screening method, we evaluated 1343 genes for their effect on depolarization in a human iPSC-derived neuron model, revealing potential links to neurodegenerative and neurodevelopmental disorders. These genes include known regulators of neuronal excitability, such as TARPs and ion channels, as well as genes associated with autism spectrum disorder and Alzheimer's disease not previously described to affect neuronal depolarization. This CRISPRi-based screening platform offers a versatile tool to uncover molecular mechanisms controlling neuronal function in health and disease.

Humans↗

PubMed2024

Histone modifications and Sp1 promote GPR160 expression in bone cancer pain within rodent models.

Bone cancer pain (BCP) affects ~70% of patients in advanced stages, primarily due to bone metastasis, presenting a substantial therapeutic challenge. Here, we profile orphan G protein-coupled receptors in the dorsal root ganglia (DRG) following tumor infiltration, and observe a notable increase in GPR160 expression. Elevated Gpr160 mRNA and protein levels persist from postoperative day 6 for over 18 days in the affected DRG, predominantly in small-diameter C-fiber type neurons specific to the tibia. Targeted interventions, including DRG microinjection of siRNA or AAV delivery, mitigate mechanical allodynia, cold, and heat hyperalgesia induced by the tumor. Tumor infiltration increases DRG neuron excitability in wild-type mice, but not in Gpr160 gene knockout mice. Tumor infiltration results in reduced H3K27me3 and increased H3K27ac modifications, enhanced binding of the transcription activator Sp1 to the Gpr160 gene promoter region, and induction of GPR160 expression. Modulating histone-modifying enzymes effectively alleviated pain behavior. Our study delineates a novel mechanism wherein elevated Sp1 levels facilitate Gpr160 gene transcription in nociceptive DRG neurons during BCP in rodents.

Animals↗

PubMed2026

Altered Excitation-Inhibition Balance and mGluR1/5-Driven Plasticity in the Motor Cortical Surface in a Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by progressive dopaminergic degeneration and maladaptive motor cortical plasticity. However, the cellular pathways underlying cortical surface activity in the primary motor cortex (M1) remain unclear, despite serving as a potential target for electrotherapy. We investigated the excitatory-inhibitory (E-I) balance and synaptic plasticity of superficial M1 circuits in a unilateral 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Using extracellular local field potential and whole-cell patch recordings from the contralateral and ipsilateral M1 hemispheres of hemi-parkinsonian rats, we observed a significantly elevated field excitatory postsynaptic potential (fEPSP) input-output function but unchanged intrinsic neuronal excitability in the M1 superficial layer. An altered relative contribution between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated transmission was reflected by a significantly increased AMPA/NMDA ratio. Markedly reduced inhibitory synaptic tone was also evidenced by the decreased amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), supporting an E-I imbalance favoring excitation in PD. Furthermore, group I metabotropic glutamate receptor (mGluR1/5)-dependent long-term depression (LTD) was abolished in the ipsilateral PD hemisphere, whereas NMDAR-dependent LTD remained intact. In summary, dopamine depletion appears to enhance network excitation and disrupt mGluR1/5-mediated control of M1 surface circuitry. Our findings identify altered cortical surface mGluR-dependent plasticity in the hemi-parkinsonian model; however, the relationship between these electrophysiological alterations and individual motor outcomes remains to be determined.

Animals↗

PubMed2026

Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.

Epilepsy genetics has often been interpreted through a useful but simplified dichotomous framework in which severe epilepsies, particularly developmental and epileptic encephalopathies, are attributed mainly to rare, high-effect variants, whereas more common epilepsies are viewed as arising largely from the cumulative effects of common, small-effect variation. Although this framework has been instrumental for gene discovery, molecular diagnosis, and mechanism-based treatment, it does not fully explain incomplete penetrance, intrafamilial phenotypic heterogeneity, or marked differences in severity among individuals sharing the same molecular diagnosis. Evidence from exome sequencing, copy number variant (CNV) studies, and genome-wide association studies increasingly suggests that rare SNVs/indels, CNVs, and common variant should not be interpreted as entirely independent risk sources, but may partially converge on shared genes, pathways, cell types, and neurobiological processes relevant to neuronal excitability, network stability, and seizure susceptibility. Here, we review evidence across epilepsy subtypes, focusing on convergence and divergence across the allelic spectrum, and discuss how polygenic background and other modifiers may influence penetrance and clinical expressivity among carriers of rare pathogenic variants and CNVs. We also consider implications for variant interpretation, genetic counseling, risk stratification, and precision medicine, while emphasizing that most rare-common integrated models remain insufficiently validated for routine clinical decision-making.

common variants↗

PubMed2026

GIRK Channels Regulate Circadian Rhythms of Excitability in Prokineticin 2 Neurons of the Suprachiasmatic Nucleus and Modulate Behavioral Circadian Rhythms.

The suprachiasmatic nucleus (SCN), the central circadian clock in mammals, generates robust yet adaptable circadian rhythms through electrically mediated coordination among heterogeneous peptidergic neuronal populations with presumed cell type-specific roles. Previous studies have proposed that circadian changes in membrane excitability of individual SCN neurons arise from time-of-day-dependent shifts in the relative balance of subthreshold Na+ and K+ conductances. Although multiple channels have been implicated in these processes, how nocturnally dominant K+ conductances are implemented in a cell type-specific manner remains poorly understood. Prokineticin 2 (Prok2) has been identified as a SCN signaling peptide essential for behavioral circadian regulation; however, the electrophysiological properties of Prok2-expressing neurons and the mechanisms underlying their diurnal rhythmicity remain largely unexplored. Here, using electrophysiological approaches in mice of either sex, we show that Prok2 neurons exhibit diurnal variations in electrical properties, with higher excitability during the day and reduced excitability at night, and that G-protein-coupled inwardly rectifying potassium (GIRK) channel-mediated basal current contributes to nighttime hyperpolarization. Immunofluorescence and single-cell RT-PCR analyses revealed that GIRK1 and GIRK3 are the predominant GIRK subunits expressed in Prok2 neurons. Moreover, Prok2 neuron-specific deletion of GIRK3 using in vivo genome editing resulted in significant nocturnal depolarization and induced abnormalities in behavioral rhythms, including delayed activity onset and circadian period lengthening, with altered SCN network activity. Together, these findings suggest that tonic, G-protein-dependent regulation of GIRK channels provides a night-specific inhibitory mechanism that contributes to intrinsic diurnal neuronal excitability in Prok2 neurons and supports the regulation of behavioral circadian rhythms.

Animals↗

PubMed2025

A Massively Parallel CRISPR-Based Screening Platform for Modifiers of Neuronal Activity.

Understanding the complex interplay between gene expression and neuronal activity is crucial for unraveling the molecular mechanisms underlying cognitive function and neurological disorders. Here, we developed pooled screens for neuronal activity, using CRISPR interference (CRISPRi) and the fluorescent calcium integrator CaMPARI2. Using this screening method, we evaluated 1343 genes for their effect on excitability in human iPSC-derived neurons, revealing potential links to neurodegenerative and neurodevelopmental disorders. These genes include known regulators of neuronal excitability, such as TARPs and ion channels, as well as genes associated with autism spectrum disorder and Alzheimer's disease not previously described to affect neuronal excitability. This CRISPRi-based screening platform offers a versatile tool to uncover molecular mechanisms controlling neuronal activity in health and disease.

Journal Article↗

PubMed2026

Biophysical mechanisms underlying the generation and maintenance of rule-learning engram.

Training rodents in a particularly difficult olfactory-discrimination task results with acquisition of high-skill to perform the task superbly, termed 'rule-learning'. We show that rule-learning occurs abruptly, in a "light-bulb moment". Using whole-cell patch-clamp recordings from the piriform cortex (PC) of Fos2A-iCreER/TRAP2 mice, we target activated-neurons, expressing immediate early genes (IEG). We notice, from the onset of training, IEG-positive neurons from trained animals display enhanced intrinsic excitability. Subsequently, synaptic excitation and inhibition are enhanced in these neurons, in a coordinated, cell-wide process. Additionally, in parallel, we detect the density of IEG-expressing neurons sharply declines. Double labeling with TRAP and c-Fos reveal that nearly two-thirds of the rule-memory cell ensemble neurons are activated from the beginning of training. Silencing TRAP-expressing neurons using inhibitory DREADD leads to a complete loss of rule memory. Hence, we propose that rule learning occurs at a discrete moment and is developed through a gradual process that stabilizes the memory of the rule.

Animals↗

PubMed2026

A compact GAD67 promoter enables inhibitory neuron-targeted AAV gene therapy for seizure suppression.

Epilepsy arises from disruption of excitation-inhibition (E/I) balance, typically due to excessive excitatory activity. Despite available therapies, a substantial proportion of patients remain treatment resistant. Enhancing inhibitory neuron activity via gene therapy can restore E/I balance and may therefore provide a therapeutic strategy for treatment-resistant epilepsy. Here, we developed a compact 410-bp glutamic acid decarboxylase 67 promoter (cmGAD67) that enables strong, selective transgene expression in inhibitory neurons while preserving adeno-associated virus (AAV) packaging capacity. Systemic delivery of AAV vectors carrying cmGAD67 preferentially targeted parvalbumin interneurons and enabled efficient circuit modulation. To evaluate therapeutic potential, we expressed glutamic acid decarboxylase 65 (GAD65) under the control of cmGAD67 (AAV-GAD65). AAV-GAD65 suppressed abnormal delta oscillations, reduced seizure-like activity, normalized anxiety-like behavior, and improved survival in seizure models. Biochemical analyses confirmed increased GABA levels in the cortex and hippocampus, linking functional improvements to enhanced inhibitory neurotransmitter synthesis. Together, these findings establish the cmGAD67 promoter as a versatile platform for inhibitory neuron-targeted AAV gene delivery and identify AAV-GAD65 as a promising strategy for seizure control and disorders associated with E/I imbalance.

Glutamate Decarboxylase↗

PubMed2025

Biosafety and efficacy of Kv7 activating rdHSV-CA8∗ analgesic gene therapy for chronic pain via the intra-articular route in mice.

Chronic pain remains a global health challenge, often resistant to available treatments with socioeconomic and psychological burdens. All chronic pain is believed due to neuronal signaling imbalances, resulting in increased excitability. Gene therapy represents a promising molecular therapy targeting molecular pain processing pathways, by offering precise, localized, long-lasting neuromodulation while minimizing systemic exposure and side effects. In model systems, replication-defective, disease-free, herpes simplex virus (rdHSV) gene therapy expressing an analgesic carbonic anhydrase-8 (CA8∗) peptide variant corrects somatosensory hyperexcitability by activating Kv7 voltage-gated potassium channels, produces profound, long-lasting analgesia and treats chronic pain from knee osteoarthritis (OA). In these studies, we provide the first non-glucagon-like peptide (GLP) biosafety, efficacy, biodistribution, shedding, and histopathology examination of this rdHSV-CA8∗. Naive mice were examined for clinical safety, biodistribution across all major tissues, knee histopathology, and analgesic efficacy via the intra-articular knee route of administration. We observed no signs of persistent toxicity, viral genomes remained where they were injected, and there was no evidence of shedding. Profound analgesia persisted for 6 months without functional impairments. These initial biosafety and efficacy data support further development of rdHSV-CA8∗ for treating chronic knee pain due to moderate to severe OA.

Animals↗

PubMed2026

Altered neural electrophysiological properties in the anterior cingulate cortex in a mouse model of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental genetic disease associated with multiple metabolic and behavioural abnormalities converging into a distinctive clinical phenotype characterized by insatiable appetite leading to hyperphagia and eventual morbid obesity. The PWS spectrum results from deficiencies in paternally imprinted chromosome 15q11-13 region clustering around non-coding RNA multiple-repeat gene Snord116. A PWS mouse model with paternal Snord116 deletion (Snord116del) revealed multiple expected behavioural traits but failed to reproduce obesity in experimental paradigms designed to uncover homeostatic hypothalamic mechanisms of hyperphagia, while the possibility for pathologic hedonic overdrive underlying hyperphagic behaviours was not studied. In Snord116del mice, we examined functional properties of pyramidal neurons (PyNs) in the anterior cingulate cortex (ACC), the brain area commonly associated with goal-oriented and choice-outcome processing, including the value assessment of food items. We found indications of higher dendritic complexity and stronger afferent excitatory connectivity compared to controls. A strong excitatory input into Snord116del PyNs was balanced by a more hyperpolarized resting membrane potential, rendering lower soma excitability, improved signal-to-noise discrimination and stronger low-pass filtering. The enhanced excitatory network-tuning ability originating from Snord116 deficiency may explain the previously reported better performance of Snord116del over wild-type mice in working-for-food behavioural tests, whereas in humans it might entail exaggerated reward-seeking behaviour since early childhood when food is the main attractant. Our analysis of previously published genomic databases revealed candidate genes responsible for the abnormal functional neuronal phenotype caused by Snord116 deletion, including K+ and Na+ voltage-dependent ion channels, protein kinases, phosphatases and components of the mechanistic target of rapamycin (mTOR) intracellular signalling pathway. KEY POINTS: Altered biophysical characteristics and parameters of neuronal connectivity in pyramidal neurons in the anterior cingulate cortex (ACC) in Snord116 deletion mice. Alterations include augmented afferent synaptic input, altered resting state and firing properties of ACC pyramidal neurons. Our findings uncover a possible mechanistic basis for altered ACC functionality in Prader-Willi syndrome.

Animals↗

PubMed2026

Alternative splicing in layer 3 pyramidal neurons differs across regions of the human cortical hierarchy.

The primate neocortex is organized as hierarchical networks of functionally distinct regions. In the dorsal visual stream network, information is conveyed from primary visual (V1) to posterior parietal (PPC) and dorsolateral prefrontal (DLPFC) cortices. This information transfer is mediated primarily by layer 3 pyramidal neurons (L3PNs), which differ across these regions in morphology, excitability, and intracellular Ca2+ regulation. These region-specific L3PN properties may be influenced by alternative splicing (AS) of pre-mRNA, which occurs extensively in the human brain. To explore the potential impact of AS of region-specific L3PN properties, we analyzed RNA-seq data from pools of L3PNs dissected from human V1, PPC, and DLPFC. We found that <6% of genes with regional differences in expression also differed in AS. This finding indicates that the absence of transcriptional differences is insufficient to conclude that a gene does not contribute functional differences between regions. Additionally, there were numerous regional differences in AS, particularly between V1 and DLPFC or PPC L3PNs, which involved genes associated with neuron morphology and Ca2+ regulation; > 90% of these AS differences involved functionally relevant sequences (eg phosphorylation sites, etc.). These findings suggest AS contributes to region-specific L3PN properties relevant to the function of the dorsal visual stream.

Humans↗

PubMed2026

STX1B variant-specific synaptic dysfunction is associated with network hyperexcitability in human iPSC-derived neurons.

BACKGROUND: Variants in STX1B/syntaxin-1B are linked to a spectrum of fever-associated epilepsy syndromes. While studies in murine models have provided mechanistic insights, their relevance to human disease in a heterozygous context may be limited. METHODS: We investigated two pathogenic STX1B variants using isolated single neurons and neuronal network cultures derived from patient-specific induced pluripotent stem cells. These carried either a de novo p.G226R variant, associated with severe developmental epilepsy, or an InDel variant (p.K45delinsRCMIE/p.L46M) linked to a transient familial seizure syndrome. Synaptic function and network excitability were assessed using patch-clamp and multi-electrode array recordings, alongside morphological and transcriptomic profiling. FINDINGS: G226R exhibited both gain- and loss-of-function characteristics, with increased miniature excitatory postsynaptic current frequency in networks but not in autapses, and synaptic failure during sustained high-frequency stimulation. For the InDel variant, the predicted loss-of-function phenotype based on reduced syntaxin-1B levels was not detectable at the single-cell level, likely masked by compensatory synaptic upregulation. At the network level, however, both variants were associated with neuronal hyperexcitability, characterised by more frequent and prolonged bursting activity, with a much stronger phenotype in G226R-containing networks. Transcriptomic profiling revealed a differential dysregulation of synaptic and other neuronal genes. INTERPRETATION: The divergence between morphological, electrophysiological and transcriptomic findings suggests that compensatory mechanisms may contribute to network hyperexcitability. Initially engaged to maintain homoeostasis, they may ultimately contribute to a pathological network state. The graded severity of network alterations across STX1B variants correlates with the clinical phenotypes. FUNDING: BMBF (Treat ION-01GM2210A, SNAREopathies-01EW1809A), 2023 FEBS Summer Fellowship, Fortüne programme (2610-0-0), EKFS college precise.net, Open Access Publishing Fund of University of Tübingen.

Humans↗

PubMed2026

CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.

Humans↗

PubMed2026

Faster N1 latency in response to homeostatic-like plasticity of PREPs is impaired during pain: A randomized-placebo capsaicin-pain study.

INTRODUCTION: Homeostatic-like plasticity (HP-like) stabilizes cortical excitability through long-term potentiation and depression-like mechanisms. The efficacy of homeostatic regulation in the corticomotor system is impaired during pain, which may have functional relevance for chronic pain. This study investigated whether a cortical HP-like response could be assessed by nociceptive stimulation, and if such response was impaired by experimental tonic pain. METHODS: Twenty-eight healthy participants completed placebo and capsaicin sessions, with 11 sham controls for time and design. HP-like plasticity was induced with two blocks of anodal tDCS over the primary motor cortex. The N1 (TP7) and N2P2 (Cz) components of electrically induced pain-related evoked potentials (PREPs) were assessed from the volar forearm before and after patch application, and again immediately and 20 min after HP-like induction. An HP-like response was defined by PREP decrease after induction, and further normalization to baseline. RESULTS: Anodal tDCS did not induce an HP-like regulation of PREP amplitudes. Interestingly, an HP-like response was observed as a fastening of N1 latency after HP-like induction, which returned to baseline values after 20 min. The latter effect was impaired during capsaicin-induced pain, where N1 was slower. The N2P2 component showed habituation over time in all sessions. CONCLUSION: This is the first study that investigates the HP-like regulation of nociceptive-evoked responses. An HP-like response was observed as a shortening of N1 latency, suggesting that early nociceptive processing may be susceptible to homeostatic regulation. In contrast, the later component, N2P2, showed habituation over time, which prevented evaluation of HP-like effects.

Humans↗