Suppression of piriform cortex alters brain-wide dynamics and alleviates seizures in temporal lobe epilepsy

Abstract

AbstractTemporal lobe epilepsy (TLE) is a pathological state that involves altered excitation-inhibition (E-I) in the brain and exhibits recurrent seizures. Many circuit studies of TLE have focused on the hippocampus. Anterior piriform cortex (APC) is also a limbic area closely associated with TLE, but is understudied. In the APC, parvalbumin-expressing (PV+) interneurons provide strong inhibition and help maintain E-I balance. However, whether APCPVneurons play a causal role in TLE is unclear.We used the systemic pilocarpine and intrahippocampal kainic acid (KA) mouse models, which showed pathological changes and spontaneous recurrent seizures (SRSs) akin to those observed in patients with TLE. Whole-cell patch clamp recording and immunohistochemistry were used to examine inhibitory synaptic transmission in the pilocarpine model. Then, using chemogenetics and multi-site local field potential (LFP) recording, we manipulated APCPVneurons at different periods, before applying convulsant, during status epilepticus (SE) and in chronic epileptic phase, and examined the efficacy of APCPVneuronal activation on seizures. For chronic period experiments, KA-injected mice underwent four-site longitudinal LFP recordings. We quantified SRSs based on the frequency and duration of epileptic discharges (> 2 Hz, 10 seconds). For the underlying functional network dynamics, we analyzed the power of each recording site and functional connectivity of each pair of regions in four epileptic states, preictal, ictal, postictal and interictal.In the pilocarpine model, we found impaired synaptic inhibition and loss of PV synapses in the APC. APCPVneuronal pre-activation decreased seizure susceptibility and mortality, but could not stop an ongoing SE. In the chronic KA model, activation of APCPVneurons reduced the frequency and duration of SRSs in the hippocampus. Interestingly, APCPVneuronal activation altered the brain-wide dynamics of seizure network and afforded differential modulation based on epileptic states, brain regions and frequency bands.Our work demonstrates the causal role of APCPVin TLE and provides detailed functional characterization of mechanisms underlying the effectiveness of APCPVactivation. We reveal how a cortical microcircuit can alter neural activity in multiple brain regions and exert antiepileptic benefits. These findings strengthen the idea that large-scale connections from APC play a key role in maintaining the E-I balance of the entire seizure network and thus provide the basis for future circuit-based therapies.