The dentate gyrus is a major locus for structural and synaptic reorganization in temporal lobe epilepsy. While physiological changes during epileptogensis are well characterized in the principal dentate projection neuron, granule cells (GCs), epilepsy-related changes in semilunar granule cells (SGCs), a distinct subset of dentate projection neurons, remain unknown. Using a mouse pilocarpine model of epilepsy, we show that, unlike GCs, SGCs exhibit an increase in intrinsic excitability 1 week after status epilepticus (SE), accompanied by a depolarized resting membrane potential in epileptic mice 1-month post-SE. Both GCs and SGCs display increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in early post-SE and epileptic mice. However, only SGCs received more frequent spontaneous inhibitory postsynaptic currents (sIPSCs) and exhibited smaller afferent-evoked IPSCs early after SE. Additionally, evoked EPSC amplitude in SGCs was reduced in epileptic mice. Behaviorally, epileptic mice showed impairments in their ability to use spatial search strategies in a Barnes maze paradigm. Epileptic TRAP::tdT mice showed reduced activity dependent neuronal ensemble labeling, with fewer tdT-labeled neurons in both task-naïve and trained conditions and reduced c-Fos co-expression following task re-acquisition compared to controls. Notably, the proportion of SGCs within labeled ensembles was reduced in task-naïve epileptic mice but not in trained animals. Collectively, our findings identify selective changes in SGC intrinsic excitability during epileptogenesis that could contribute to enhanced network excitability. The cell-specific alterations in SGC circuit connectivity during epileptogenesis, alongside the apparent reduction in neuronal recruitment to behavioral ensembles likely contribute to spatial navigation deficits observed in epilepsy.
Dovek et al. (Mon,) studied this question.