Seizure-induced strengthening of a recurrent excitatory circuit in the dentate gyrus is proconvulsant

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(32)

Published: Aug. 5, 2022

Epilepsy is a devastating brain disorder for which effective treatments are very limited. There growing interest in early intervention, requires better mechanistic understanding of the stages this disorder. While diverse insults can lead to epileptic activity, common cellular mechanism relies on uncontrolled recurrent excitatory activity. In dentate gyrus, mossy cells (MCs) project extensively onto granule (GCs) throughout hippocampus, thus establishing MC-GC-MC loop. MCs implicated temporal lobe epilepsy, form but their role during initial seizures (i.e., before characteristic MC loss that occurs late stages) unclear. Here, we show acutely induced with an intraperitoneal kainic acid (KA) injection adult mice, well-established model leads experimental not only increased and GC activity vivo also triggered brain-derived neurotrophic factor (BDNF)-dependent long-term potentiation (LTP) at MC-GC synapses. Moreover, induction LTP using MC-selective optogenetic stimulation worsened KA-induced seizures. Conversely,

Language: Английский

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Microglia sense and suppress epileptic neuronal hyperexcitability

Pharmacological Research, Journal Year: 2023, Volume and Issue: 195, P. 106881 - 106881

Published: Aug. 2, 2023

Microglia are the resident immune cells of central nervous system, undertaking surveillance role and reacting to brain homeostasis neurological diseases. Recent studies indicate that microglia modulate epilepsy-induced neuronal activities, however, mechanisms underlying microglia-neuron communication in epilepsy still unclear. Here we report epileptic hyperexcitability activates drives microglial ATP/ADP hydrolyzing ectoenzyme CD39 (encoded by Entpd1) expression via recruiting cAMP responsive element binding protein (CREB)-regulated transcription coactivator-1 (CRTC1) from cytoplasm nucleus CREB. Activated turn suppress a dependent manner. Disrupting CREB/CRTC1 signaling, decreases diminishes inhibitory effect on hyperexcitability. Overall, our findings reveal CD39-dependent control is through an excitation-transcription coupling mechanism.

Language: Английский

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Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 21, 2023

Abstract The type-1 cannabinoid receptor (CB 1 R) is widely expressed in excitatory and inhibitory nerve terminals, by suppressing neurotransmitter release, its activation modulates neural circuits brain function. While the interaction of CB R with various intracellular proteins thought to alter signaling, identity role these are poorly understood. Using a high-throughput proteomic analysis complemented an array vitro vivo approaches mouse brain, we report that C -terminal, domain interacts specifically growth-associated protein 43 kDa (GAP43). R-GAP43 occurs selectively at mossy cell axon boutons, which establish synapses dentate granule cells hippocampus. This impairs R-mediated suppression transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity mice. Thus, GAP43 acts as synapse type-specific regulatory partner hampers effects on hippocampal circuit

Language: Английский

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Optogenetics for controlling seizure circuits for translational approaches

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 184, P. 106234 - 106234

Published: July 20, 2023

The advent of optogenetic tools has had a profound impact on modern neuroscience research, revolutionizing our understanding the brain. These offer remarkable ability to precisely manipulate specific groups neurons with an unprecedented level temporal precision, order milliseconds. This breakthrough significantly advanced knowledge various physiological and pathophysiological processes in Within realm epilepsy have played crucial role investigating contributions different neuronal populations generation seizures hyperexcitability. By selectively activating or inhibiting using optogenetics, researchers been able elucidate underlying mechanisms identify key players involved epileptic activity. Moreover, techniques also explored as innovative therapeutic strategies for treating epilepsy. aim halt seizure progression alleviate symptoms by utilizing precise control offered optogenetics. application provided valuable insights into intricate workings brain during episodes. For instance, discovered how distinct interneuron contribute initiation (ictogenesis). They revealed remote circuits regions such cerebellum, septum, raphe nuclei can interact hyperexcitable networks hippocampus. Additionally, studies demonstrated potential closed-loop systems, where optogenetics is combined real-time monitoring, enable precise, on-demand Despite immense promise approaches, it important acknowledge that many these are still early stages development yet reach clinical applications. transition from experimental research practical use poses numerous challenges. In this review, we introduce tools, provide comprehensive survey their critically discuss current limitations achieving successful implementation treatment human addressing aspects, hope foster deeper state future prospects treatment.

Language: Английский

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Chronic optogenetic stimulation of dentate gyrus granule cells in mouse organotypic slice cultures synaptically drives mossy cell degeneration

Epilepsia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Abstract Objective Degeneration of hilar mossy cells in the dentate gyrus is an important hallmark hippocampal sclerosis and often observed patients with temporal lobe epilepsy. To understand pathogenesis develop novel neuroprotective treatments, it critical to determine mechanistic processes cell degeneration factors that influence vulnerability or resilience. However, suitable vitro approaches are currently lacking. We have developed validated organotypic slice culture‐based model facilitates studies activity‐dependent Methods A was using entorhino‐hippocampal cultures. Dentate granule were transduced adeno‐associated viruses express channelrhodopsin2. Transduced cultures chronically stimulated by light, resulting damage assessed propidium iodide staining. Spontaneous synaptic activity before after optical stimulation recorded whole‐cell patch‐clamp. Results Selective dose‐dependent neuron following chronic optogenetic expressing channelrhodopsin‐2 cells. Treatment anticonvulsant retigabine reduced stimulation‐induced loss a manner. This demonstrates suitability our for drug screening. Patch‐clamp recordings verified strong activation during reduction spontaneous excitatory stimulation. Significance The role context epileptic seizures has been controversial topic discussion. presented allows study on single‐cell level provides first evidence changes will facilitate understanding epilepsy, providing foundation therapeutic interventions aimed at preserving function epilepsy patients.

Language: Английский

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Biophysical characterization and modelling of SCN1A gain-of-function predicts interneuron hyperexcitability and a predisposition to network instability through homeostatic plasticity

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 179, P. 106059 - 106059

Published: March 2, 2023

SCN1A gain-of-function variants are associated with early onset developmental and epileptic encephalopathies (DEEs) that possess distinct clinical features compared to Dravet syndrome caused by loss-of-function. However, it is unclear how may predispose cortical hyper-excitability seizures. Here, we first report the of a patient carrying de novo variant (T162I) neonatal-onset DEE, then characterize biophysical properties T162I three other DEE (I236V) infantile (P1345S, R1636Q). In voltage clamp experiments, (T162I, P1345S R1636Q) exhibited changes in activation inactivation enhanced window current, consistent gain-of-function. Dynamic action potential experiments utilising model neurons incorporating Nav1.1. channels supported mechanism for all four variants. T162I, I236V, P1345S, R1636Q higher peak firing rates relative wild type produced hyperpolarized threshold reduced neuronal rheobase. To explore impact these upon excitability, used spiking network containing an excitatory pyramidal cell (PC) parvalbumin positive (PV) interneuron population. was modelled enhancing excitability PV interneurons simple forms homeostatic plasticity restored rates. We found mechanisms exerted differential function, PV-to-PC PC-to-PC synaptic strength predisposing instability. Overall, our findings support role inhibitory hyperexcitability DEE. propose through which pathways can pathological activity contribute phenotypic variability disorders.

Language: Английский

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TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Dec. 19, 2023

Abstract Background Excess tumor necrosis factor (TNF) is implicated in the pathogenesis of hyperinflammatory experimental cerebral malaria (eCM), including gliosis, increased levels fibrin(ogen) brain, behavioral changes, and mortality. However, role TNF eCM within brain parenchyma, particularly directly on neurons, remains underdefined. Here, we investigate electrophysiological consequences neuronal excitability cell signaling mechanisms that contribute to observed phenotypes. Methods The split-luciferase complementation assay (LCA) was used downstream receptor 1 (TNFR1) could changes eCM. Whole-cell patch-clamp electrophysiology performed slices from mice elucidate infection CA1 pyramidal neuron Involvement identified molecules mediating sickness behavior were investigated vivo using genetic silencing. Results Exploring underlie TNF-induced effects excitability, found complex assembly fibroblast growth 14 (FGF14) voltage-gated Na + (Na v ) channel 1.6 1.6) upon stimulation via Janus Kinase 2 (JAK2). On account dependency (eCM) TNF, studies showed Plasmodium chabaudi augments conductance neurons through TNFR1–JAK2–FGF14–Na network, which leads hyperexcitability. Hyperexcitability caused by mitigated an anti-TNF antibody silencing FGF14 CA1. Furthermore, knockdown reduced infection. Conclusions may represent a therapeutic target for mitigating TNF-mediated neuroinflammation.

Language: Английский

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Retrograde adenosine/A2A receptor signaling facilitates excitatory synaptic transmission and seizures

Cell Reports, Journal Year: 2024, Volume and Issue: 43(7), P. 114382 - 114382

Published: June 19, 2024

Retrograde signaling at the synapse is a fundamental way by which neurons communicate and neuronal circuit function fine-tuned upon activity. While long-term changes in neurotransmitter release commonly rely on retrograde signaling, mechanisms remain poorly understood. Here, we identified adenosine/A

Language: Английский

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Dopamine D2 receptors in hilar mossy cells regulate excitatory transmission and hippocampal function

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(50)

Published: Dec. 8, 2023

Hilar mossy cells (MCs) are principal excitatory neurons of the dentate gyrus (DG) that play critical roles in hippocampal function and have been implicated brain disorders such as anxiety epilepsy. However, mechanisms by which MCs contribute to DG disease poorly understood. A defining feature is promoter activity dopamine D2 receptor (D2R) gene ( Drd2 ), previous work indicates a key role for dopaminergic signaling DG. Additionally, involvement D2R cognition neuropsychiatric conditions well known. Surprisingly, though, MC D2Rs remains largely unexplored. In this study, we show selective conditional removal from adult mice impaired spatial memory, promoted anxiety-like behavior, was proconvulsant. To determine subcellular expression MCs, used knockin mouse revealed enriched inner molecular layer DG, where establish synaptic contacts with granule (GCs). activation exogenous endogenous reduced GC transmission, most likely presynaptic mechanism. contrast, had no significant impact on inputs passive active properties. Our findings support essential proper reducing drive onto GCs. Lastly, impairment could promote epilepsy, therefore highlighting potential therapeutic target.

Language: Английский

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A novel rat model of Dravet syndrome recapitulates clinical hallmarks

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 184, P. 106193 - 106193

Published: June 8, 2023

Dravet syndrome (DS) is a debilitating infantile epileptic encephalopathy characterized by seizures induced high body temperature (hyperthermia), sudden unexpected death in epilepsy (SUDEP), cognitive impairment, and behavioral disturbances. The most common cause of DS haploinsufficiency the SCN1A gene, which encodes voltage-gated sodium channel Nav1.1. In current mouse models DS, phenotype strictly dependent on genetic background exhibit drastically higher SUDEP rates than patients. Therefore, we sought to develop an alternative animal model for DS. Here, report generation characterization Scn1a halploinsufficiency rat disrupting allele. Scn1a+/- rats show reduced expression cerebral cortex, hippocampus thalamus. Homozygous null die prematurely. Heterozygous animals are highly susceptible heat-induced seizures, clinical hallmark but otherwise normal survival, growth, behavior without seizure induction. Hyperthermia-induced activate distinct sets neurons hypothalamus rats. Electroencephalogram (EEG) recordings reveal characteristic ictal EEG with amplitude bursts significantly increased delta theta power. After initial hyperthermia-induced non-convulsive, convulsive occur spontaneously conclusion, generate phenotypes closely resembling providing unique platform establishing therapies

Language: Английский

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