Biology subjects

Crepel, V.

Publications and source records attributed to Crepel, V..

6 recordsLinked to original sources

bioRxiv2026

Kainate receptors are critical for permissivity to sustained, disorganized and network-wide pathological activity in the epileptic dentate gyrus

In temporal lobe epilepsy, the dentate gyrus (DG) undergoes extensive reorganization through recurrent mossy fiber (rMF) sprouting, involving both AMPA and kainate receptors (KARs) at granule cell-to-granule cell (GC-GC) recurrent synapses. While KARs are known to enhance neural excitability, their specific contribution to the dynamics of the epileptogenic GC-GC network remains poorly understood. Here, by building and assessing a DG network model endowed with KARs, we revealed that the slow excitatory postsynaptic potentials (EPSPs) they mediate, in synergy with persistent sodium currents, profoundly reshape epileptogenic dynamics by facilitating the conditions for pathological activity, through two complementary mechanisms. Regarding input processing, KARs extended the window for temporal integration in GCs, favoring the initiation of network aberrant activities in response to more dispersed input patterns. Concerning network interactions, KARs reduced the number of sprouted connections needed for the development of epileptiform discharges. In fact, the extension of the structural and functional parameter region driving epileptiform activity was effective both for their initiation and, critically, their sustained maintenance. Moreover, KARs drove a striking transition in network behaviour, from partially organized collective dynamics to a highly disordered regime. In their presence, massive firing propagated through the DG network, disrupting spatial and temporal spiking patterns. This resulted in increased activity dimensionality and entropy, together with reduced mutual information between neurons. Altogether, our results suggest that KARs are not merely amplifiers of network excitation but critical determinants that fundamentally reshape the dynamical landscape, rendering the sprouted DG network permissive to self-sustaining pathological activity.

neuroscience↗

bioRxiv2023

Pathogenic MTOR somatic variant causing focal cortical dysplasia drives hyperexcitability via overactivation of neuronal GluN2C NMDA receptors

ObjectiveGenetic variations in proteins of the mechanistic target of rapamycin (mTOR) pathway cause a spectrum of neurodevelopmental disorders often associated with brain malformations and with intractable epilepsy. The mTORopathies are characterized by hyperactive mTOR pathway and comprise tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. How hyperactive mTOR translates into abnormal neuronal activity and hypersynchronous network remains to be better understood. Previously, the role of upregulated GluN2C-containing glutamate- gated NMDA receptors (NMDARs) has been demonstrated for germline defects in the TSC genes. Here, we questioned whether this mechanism would expand to other mTORopathies in the different context of a somatic genetic variation of the MTOR protein recurrently found in FCD type II. MethodsWe used a rat model of FCD created by in utero electroporation of neural progenitors of dorsal telencephalon with expression vectors encoding either the wild-type or the pathogenic MTOR variant (p.S2215F). In this mosaic configuration, patch-clamp whole-cell recordings of the electroporated, spiny stellate neurons and extracellular recordings of the electroporated areas were performed in neocortical slices. Selective inhibitors were used to target mTOR activity and GluN2C- mediated currents. ResultsNeurons expressing the mutant protein displayed an excessive activation of GluN2C NMDAR-mediated spontaneous excitatory post-synaptic currents. GluN2C-dependent increase in spontaneous spiking activity was detected in the area of electroporated neurons in the mutant condition and was restricted to a critical time-window between postnatal days P9 and P20. SignificanceSomatic MTOR pathogenic variant recurrently found in FCD type II resulted in overactivation of GluN2C-mediated NMDARs in neocortices of rat pups. The related and time- restricted hyperexcitability was sensitive to subunit GluN2C-specific blockade. Our study suggests that GluN2C-related pathomechanisms might be shared in common by mTOR pathway-related cortical dysplasia. Key pointsO_LIExcessive activation of GluN2C NMDAR-mediated currents in spiny stellate neurons expressing FCD-causing MTOR somatic variation C_LIO_LIGluN2C-dependent increase in spontaneous spiking activity in rat somatosensory cortex containing mutant MTOR-expressing neurons C_LIO_LIGluN2C-dependent excessive network activity is time-restricted to a critical period between P9 and P20 C_LI

neuroscience↗

bioRxiv2023

GluK2 is a target for gene therapy in drug-resistant Temporal Lobe Epilepsy

ObjectiveTemporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule cells (DGCs) creates an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5-containing kainate receptors (KARs). TLE patients are often resistant to anti-seizure medications and suffer significant comorbidities; hence there is an urgent need for novel therapies. Previously we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE. MethodsWe combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug-resistant TLE. ResultsHere we confirmed the translational potential of KAR suppression using a non-selective KAR antagonist that markedly attenuated Interictal-like Epileptiform Discharges (IEDs) in TLE patient-derived hippocampal slices. An adeno-associated virus (AAV) serotype-9 vector expressing anti-grik2 miRNA was designed to specifically downregulate GluK2 expression. Direct delivery of AAV9-anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs. InterpretationOur gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof-of-concept for a gene therapy approach targeting GluK2 KARs for drug-resistant TLE patients.

neuroscience↗

bioRxiv2023

A class-specific effect of dysmyelination on the excitability of hippocampal interneurons

The role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.1B is implicated in the organization of the nodes of Ranvier as a linker between paranodal and juxtaparanodal membrane proteins to the spectrin cytoskeleton. In the present study, 4.1B KO mice are used as a genetic model to analyze the functional role of myelin in Lhx6-positive parvalbumin and somatostatin neurons, two major classes of GABAergic neurons in the hippocampus. We show that deletion of 4.1B induces disruption of juxtaparanodal K+ channel clustering and mislocalization of nodal or heminodal Na+ channels. Strikingly, 4.1B-deficiency causes loss of myelin in GABAergic axons in the hippocampus. In particular, stratum oriens O-LM cells display severe axonal dysmyelination and a reduced excitability. This reduced excitability is associated with a decrease in occurrence probability of small amplitude synaptic inhibitory events on pyramidal cells. In contrast, stratum pyramidale fast-spiking basket cells do not appear affected. The aberrant myelination of hippocampal interneurons is also correlated with impairment of spatial memory in 4.1B KO mice. In conclusion, our results indicate a class-specific effect of dysmyelination on the excitability of hippocampal interneurons associated with a functional alteration of inhibitory drive and impairment of spatial memory.

neuroscience↗

bioRxiv2019

DYRK1A up-regulation specifically impairs a presynaptic form of long-term potentiation

Chromosome 21 DYRK1A kinase has long been associated with a variety of psychiatric diseases including Down Syndrome. We previously showed that Dyrk1A interacts with SWI/SNF (SWItch/Sucrose Non-Fermentable) nucleosome remodeling complex inducing expression changes of genes encoding key neuronal proteins. However, the functional impact of this kinase at the synapse level remains unclear. We studied a mouse model that incorporated the YAC 152F7 (570 kb) encoding six chromosome 21 genes including DYRK1A. We found that DYRK1A Interacts with the key chromatin remodelers EP300 and CREBBP. Moreover, we observed changes in the transcriptional levels of genes encoding presynaptic proteins involved in glutamate vesicle exocytosis, namely Rims1, Munc13-1, Syn2, Rab3A. This result prompted us to investigate the two main forms of long-term potentiation (LTP) required for learning and memory: the (N-methyl d-aspartate) receptor-dependent postsynaptic form versus the glutamate release-dependent presynaptic form. Interestingly, extracellular electrophysiological recordings in hippocampal slices of the YAC mouse line revealed that only the presynaptic forms of plasticity were impacted, leaving the post-synaptic form of plasticity intact. T o refine our findings, we used a mouse BAC 189N3 (152 kb) line that only triplicate the gene Dyrk1A. Again, we found that this presynaptic form of LTP is also impaired in this mouse line. This result demonstrates that abnormal up-regulation of Dyrk1A alone is sufficient to inhibit specifically the presynaptic forms of LTP. Altogether, our results suggest that impairment of DYRK1A gene dosage may impact memory precision, and therefore reinforce our mechanistic understanding of the cognitive impairment detected in this mouse model.

neuroscience↗

bioRxiv2018

Mature dentate granule cells show different intrinsic properties depending on the behavioural context of their activation

The dentate gyrus (DG) plays a crucial role in learning, memory and spatial navigation. Only a small fraction of mature dentate granule cells (mDGCs) is active during behavior, while the large majority remains silent. To date, the properties of this active subset of neurons remain poorly investigated. Using fosGFP transgenic mice, we show ex vivo that activated mDGCs, from mice maintained in their home cage, exhibit a marked lower intrinsic excitability compared to the non-activated cells. Remarkably, activated mDGCs, from mice trained in a virtual environment, are more excitable than those from mice maintained in their home cage. Therefore, we show that activated mDGCs display different intrinsic properties and excitable states depending on the context of their activation. We propose that these properties could constitute a neural signature of cell assemblies recruited in different behavioral contexts.

neuroscience↗