Valérie Crépel

Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy, characterized by significant reorganization of hippocampal neuronal circuits. While changes in GABAergic inhibitory circuits are a major feature of this reorganization, other prominent alterations include hippocampal myelination disruption, neuronal loss, and pronounced glial and inflammatory responses. Recent studies have established that parvalbumin (PV +) interneurons in the hippocampus are partially myelinated under normal conditions, representing a notable structural feature of this interneuron subtype. However, whether interneuron myelination becomes altered in TLE has remained unexplored. Using a mouse TLE model, we investigated CA1 PV+ interneurons during epileptogenesis and chronic disease phases, examining numerical density and myelination patterns. We simultaneously tracked microglial responses and oligodendrocyte lineage cell populations (mature oligodendrocytes and their precursors). Our findings reveal that CA1 PV+ interneurons maintain their numerical density throughout disease progression but undergo marked myelination alterations. This dysmyelination occurs concurrently with pronounced microgliosis and changes in the dynamics of oligodendrocyte lineage cell populations, predominantly during epileptogenesis. Notably, pharmacological intervention with GW2580, a CSF1R inhibitor, administered for 8 days around the status epilepticus, prevented both PV+ interneuron myelination alterations and changes in oligodendrocyte lineage cell populations by blocking microglial proliferation. These results establish a link between microgliosis and alterations of myelin patterning in CA1 PV+ interneurons, advancing our understanding of interneuronopathy and TLE pathophysiology. The mechanisms identified share remarkable similarities with those observed in dysmyelinating and neurodegenerative diseases, including multiple sclerosis, suggesting potential common therapeutic targets.

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.

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 (PV) and somatostatin (SST) neurons, two major classes of GABAergic neurons in the hippocampus. We show that 4.1B-deficiency 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 SST 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 PV cells do not appear affected. 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.

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.

Significance: Synapses connecting granule cells to Purkinje neurons are considered essential sites for learning in the cerebellum. Strikingly, most of them appear to be silent: they do not transmit any electrical information. This may relate to information storage capacity and reliability, which are expected to improve during postnatal maturation. Here, we quantify the proportion of silent synapses in mice by combining optogenetic mapping of synaptic inputs and Purkinje neuron patch-clamp recording. We show that this proportion remains stable between the stage immediately following the postnatal establishment of cerebellar circuitry and 3 wk later when cerebellar function has maturated, presumably as a result of natural learning processes. Our results suggest that information storage capacity and reliability are optimized early during cerebellar maturation.

The dentate granule cells (DGCs) play a crucial role in learning and memory. Many studies have described the role and physiological properties of these sparsely active neurons using different behavioral contexts. However, the morpho-functional features of DGCs recruited in mice maintained in their home cage (without training), considered as a baseline condition, have not yet been established. Using fosGFP transgenic mice, we observed ex vivo that DGCs recruited in animals maintained in the home cage condition are mature neurons that display a longer dendritic tree and lower excitability compared with non-activated cells. The higher GABA_A receptor-mediated shunting inhibition contributes to the lower excitability of DGCs activated in the home environment by shifting the input resistance towards lower values. Remarkably, that shunting inhibition is neither observed in non-activated DGCs nor in DGCs activated during training in virtual reality. In short, our results suggest that strong shunting inhibition and reduced excitability could constitute a distinctive neural signature of mature DGCs recruited in the context of the home environment.

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.

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.