ADDRESSING THE GABAERGIC (HUB) NEURON DYSFUNCTION IN MESIAL TEMPORAL LOBE EPILEPSY

Mesial temporal lobe epilepsy (MTLE) is the most common form of epilepsy and approximately one third of patients are pharmaco-resistant. The imbalance between neuronal excitation/inhibition processes contributes to seizures with GABAergic transmission being particularly affected; however, distinct subpopulations of GABAergic neurons could be affected differentially. We are particularly focused on GABAergic hub neurons that have been classified as early-born and highly functionally-connected neurons that, thanks to their extensive axonal arborization, play a key role in orchestrating neural circuits’ dynamics. We thus hypothesize that hub interneurons become dysfunctional in epileptic hippocampal circuits. To test our hypothesis, we first used hippocampal organotypic slice cultures treated with picrotoxin (GABA_A receptor inhibitor) transiently for 3 days to dissect the functional connectivity of neurons and GABAergic hubs using calcium sensors. Second, we targeted in vivo early-born GABAergic neurons (i.e. GABAergic hubs) by viral injections at embryonic stage E12. MTLE was induced by intrahippocampal injection of kainic acid (KA) at 2.22mM. Data from in vitro hippocampal circuits suggests that hub interneurons are functionally re-organized suggesting a loss of hubness and hierarchy following epileptogenesis. Furthermore, KA-injected mice exhibited particularly depleted E12-labelled GABAergic neurons in the ipsilateral hippocampus. Next, we would like to target putative hub interneurons and manipulate them to study the impact on epileptogenic neural dynamics.