ABSTRACT A deeper understanding of the molecular, cellular, and circuit mechanisms that contribute to intractable epilepsy is of critical importance for improving existing therapeutic approaches. Rodent epilepsy models provide an important approach for achieving this goal and for the preclinical exploration of novel treatments. Here we focus on two types of mouse models relevant to drug-resistant seizure disorders in humans: the pilocarpine status epilepticus model (PILO-SE) of acquired temporal lobe epilepsy (TLE) and a mouse model with a genetic variant in voltage-gated ion channels that cause seizure disorders in humans. TLE shows a characteristic pattern of hippocampal neurodegeneration termed mesial temporal sclerosis (MTS), with substantial loss of pyramidal neurons in the CA1 and CA3 regions and a relative sparing of dentate gyrus (DG) and CA2 regions. Survival of DG and CA2 has led to the hypotheses that both are important for seizure activity. Although the role of DG has been well studied in rodent models, the role of CA2 has remained relatively unexplored. In the previous funding period, we found that PILO-SE leads to increased overall CA2 excitation, due to increased intrinsic excitability, enhanced synaptic excitation from DG and reduced synaptic inhibition. Importantly, we found that chronic chemogenetic or acute closed-loop optogenetic silencing of CA2 led to a significant decrease in seizure activity in PILO-SE mice. However, our previous analyses were restricted to dorsal CA2. We will address here the role of ventral CA2, as studies in both humans and rodent models suggest that ventral hippocampus may be an even more important site for seizures in TLE than dorsal hippocampus. We will therefore investigate the hypothesis that chemogenetic and/or optogenetic silencing of ventral CA2 will be even more effective in reducing seizures than observed upon silencing dorsal CA2. Our previous studies also left open the question as to whether the increase in CA2 excitation in PILO-SE is causally related to the role of CA2 in seizures. We will address this question by asking whether interventions that restore normal levels of CA2 intrinsic excitability can rescue seizures in PILO-SE. Such experiments have the advantage over genetic-based silencing as they will not interfere with the normal role of CA2 in hippocampal-dependent social memory. In addition to acquired forms of epilepsy, an increasing number of cases of epilepsy have been shown to be caused by genetic variants, some associated with MTS and others without MTS. Here we address whether CA2 may play a more general role in seizure activity by investigating its role in a mouse model of a genetic form of epilepsy caused by mutations in the gene encoding the HCN1 voltage-gated ion channel, and testing whether CA2 silencing can suppress seizures in this model. The experiments of this proposal thus offer the promise of further validating CA2 as target for novel therapeutic approaches fo...