Chemogenetic activation of parvalbumin interneurons in the piriform cortex alleviates hippocampal focal seizures

BackgroundTemporal lobe epilepsy (TLE) involves aberrant changes in the brain at molecular, cellular and circuitry levels, leading to recurrent seizures. Approximately one-third of patients develop drug resistance. Circuit-based interventions show promise for alleviating the drug-resistant seizures. This study explored the efficacy of chemogenetic stimulation on specific neuronal populations in piriform cortical microcircuits in a mouse TLE model. ObjectiveThe anterior piriform cortex (APC) is a limbic area closely associated with TLE but is understudied. Our previous study demonstrated that in the APC, parvalbumin-expressing (PV+) interneurons provide strong inhibition and help maintain excitation-inhibition balance. Here, we examined whether and how APCPV neurons can ameliorate seizure symptoms in TLE. MethodsWe used a chronic intrahippocampal kainic acid (IHKA) mouse model that develops hippocampal pathology and spontaneous recurrent seizures (SRSs). APCPV neurons were chemogenetically activated, and local field potentials were recorded longitudinally from multiple regions. Seizure metrics, spectral power and functional connectivity were compared between APCPV-activated and control samples. ResultsLoss of PV+ synapses emerged in the APC during epileptogenesis. Selective activation of APCPV neurons reduced the frequency and duration of hippocampal SRSs and modified long-range dynamics, with region- and frequency-specific changes in interictal band power and functional connectivity. ConclusionAPCPV chemogenetic activation exerts a robust anti-seizure effect and identifies the APC as a promising cortical node for seizure network control. The associated spectral and connectivity signatures suggest that targeted modulation of APC microcircuits can rebalance distributed seizure networks and lower seizure recurrence.