Hippocampal area CA2 controls seizure dynamics, interictal EEG abnormalities and social comorbidity in mouse models of temporal lobe epilepsy

Abstract

Temporal lobe epilepsy (TLE) is characterized by spontaneous recurrent seizures, abnormal activity between seizures, and impaired behavior. CA2 pyramidal neurons (PNs) are potentially important because inhibiting them with a chemogenetic approach reduces seizure frequency in a mouse model of TLE. However, whether seizures could be stopped by timing inhibition just as a seizure begins is unclear. Furthermore, whether inhibition would reduce the cortical and motor manifestations of seizures are not clear. Finally, whether interictal EEG abnormalities and TLE comorbidities would be improved are unknown. Therefore, real-time optogenetic silencing of CA2 PNs during seizures, interictal activity and behavior were studied in 2 mouse models of TLE. CA2 silencing significantly reduced seizure duration and time spent in convulsive behavior. Interictal spikes and high frequency oscillations were significantly reduced, and social behavior was improved. Therefore, brief focal silencing of CA2 PNs reduces seizures, their propagation, and convulsive manifestations, improves interictal EEG, and ameliorates social comorbidities. HIGHLIGHTSO_LIReal-time CA2 silencing at the onset of seizures reduces seizure duration C_LIO_LIWhen CA2 silencing reduces seizure activity in hippocampus it also reduces cortical seizure activity and convulsive manifestations of seizures C_LIO_LIInterictal spikes and high frequency oscillations are reduced by real-time CA2 silencing C_LIO_LIReal-time CA2 silencing of high frequency oscillations (>250Hz) rescues social memory deficits of chronic epileptic mice C_LI