Hippocampal microcircuits constrain the generation of epileptiform activity

Epilepsy is largely characterized using macroscale measures of neural activity, such as electroencephalography, which are unable to resolve the underlying cellular-level substrates of pathological activity. Although there is a growing understanding that hippocampal microcircuits, comprised of distinct CA1 principal cells (PCs), inhibitory neurons, and input/output relationships, route information through parallel hippocampal pathways, the relevance of this microscale organization in epilepsy is poorly understood. To address this gap, we focally knocked out the β3 subunit of the GABA_A receptor from CA1 PCs, which strongly impaired parvalbumin-mediated inhibition to deep PCs, but not superficial PCs - potentially promoting a microcircuit-selective epilepsy manifestation. Indeed, we observed robust interictal epileptiform discharges (IEDs) at the site of focal knockout with features consistent with a potential CA2-to-deep CA1 PC generation mechanism. In line with prior observations that CA2 inputs potently drive deep PCs under physiological conditions, IEDs could be reliably evoked by optogenetic stimulation of CA2 in β3 focal knockout mice. Resolving cellular activity across the CA1 PC network during IEDs, in vivo 2-photon calcium imaging demonstrated stronger activation of deep versus superficial PCs. Altogether, these data demonstrate that macroscopic electrophysiological patterns such as IEDs can have underlying microcircuit constraints, which has important implications for designing therapies that target the underlying microcircuit generators of epileptiform activity.