Reduced Cholecystokinin-Expressing Interneuron Input Contributes to Disinhibition of the Hippocampal CA2 Region in a Mouse Model of Temporal Lobe Epilepsy.

A significant proportion of temporal lobe epilepsy (TLE) patients experience drug-resistant seizures associated with mesial temporal sclerosis, in which there is extensive cell loss in the hippocampal CA1 and CA3 subfields, with a relative sparing of dentate gyrus granule cells and CA2 pyramidal neurons (PNs). A role for CA2 in seizure generation was suggested based on findings of a reduction in CA2 synaptic inhibition (Williamson and Spencer, 1994) and the presence of interictal-like spike activity in CA2 in resected hippocampal tissue from TLE patients (Wittner et al., 2009). We recently found that in the pilocarpine-induced status epilepticus (PILO-SE) mouse model of TLE there was an increase in CA2 intrinsic excitability associated with a loss of CA2 synaptic inhibition. Furthermore, chemogenetic silencing of CA2 significantly reduced seizure frequency, consistent with a role of CA2 in promoting seizure generation and/or propagation (Whitebirch et al., 2022). In the present study, we explored the cellular basis of this inhibitory deficit using immunohistochemical and electrophysiological approaches in PILO-SE male and female mice. We report a widespread decrease in the density of pro-cholecystokinin-immunopositive (CCK1) interneurons and a functional impairment of CCK1 interneuron-mediated inhibition of CA2 PNs. We also found a disruption in the perisomatic perineuronal net in the CA2 stratum pyramidale. Such pathologic alterations may contribute to an enhanced excitation of CA2 PNs and CA2-dependent seizure activity in the PILO-SE mouse model. [ABSTRACT FROM AUTHOR]