Circuit reorganization of subicular cell-type-specific interneurons in temporal lobe epilepsy

Abstract

The subiculum represents a crucial brain pivot in regulating seizure generalization in temporal lobe epilepsy (TLE), primarily through synergy of local GABAergic and long-projecting glutamatergic signaling. However, little is known about how subicular GABAergic interneurons are involved in a cell-type-specific way. Here, employing Ca²⁺ fiber photometry, retrograde monosynaptic viral tracing and chemogenetics in epilepsy models of both male and female mice, we elucidate circuit reorganization patterns mediated by subicular cell-type-specific interneurons and delineate their functional disparities in seizure modulation in TLE. We reveal distinct functional dynamics of subicular parvalbumin+ and somatostatin+ interneurons during secondary generalized seizure. These interneuron subtypes have their biased circuit organizations in terms of both input and output patterns, which undergo distinct reorganization in chronic epileptic condition. Notably, somatostatin+ interneurons exert more effective feedforward inhibition onto pyramidal neurons compared to parvalbumin+ interneurons, which engenders consistent anti-seizure effects in TLE. These findings provide an improved understanding of different subtypes of subicular interneurons in circuit reorganization in TLE, and supplement compelling proofs for precise treatment of epilepsy by targeting subicular somatostatin+ interneurons.

Significance statement Temporal lobe epilepsy (TLE) is the most common type of refractory epilepsy and not well controlled by current medications. In this study, we reveal that subicular GABAergic interneurons are involved in seizure generalization in a cell-type-specific way. We find subicular parvalbumin+ and somatostatin+ interneurons have distinct functional dynamics and undergo different circuit reorganizations in chronic epileptic condition. Notably, somatostatin+ interneurons exert more effective inhibition onto pyramidal neurons, engendering consistent anti-seizure effects. This is therapeutically significant for precise treatment targeting the subiculum in TLE.