Ventral subicular pyramidal neurons contribute to epileptogenesis via anterior thalamic circuit

The subiculum contains functionally distinct dorsal and ventral subdivisions and is implicated in temporal lobe epilepsy (TLE). Yet, the contribution of ventral subicular glutamatergic neurons (vSub^glu) to epileptogenesis remains unclear. Using in vivo fiber photometry and c-Fos mapping in a hippocampal-kindling TLE model, we identified pronounced hyperactivation of vSub^glu during seizure development. Optogenetic activation of vSub^glu alone recapitulated the kindling process and accelerated kindling progression when applied following electrical stimulation. Conversely, optogenetic or chemogenetic inhibition of vSub^glu robustly suppressed seizure development in both the kindling model and the acute KA model and delayed epileptogenesis in the chronic KA model. Circuit-specfic manipulations revealed that the pro-epileptic effects are mediated predominantly through glutamatergic projections from the vSub to the anterior thalamic glutamatergic neurons (ATN^glu). This vSub^glu-ATN^glu circuit exhibited both necessity and sufficiency for epileptogenesis in the kindling model, as evidenced by pathway-specific manipulations. Collectively, our findings uncover a previously unrecognized hippocampo-thalamic circuit that critically governs epileptogenesis in TLE, highlighting vSub^glu-ATN^glu circuit as a promising target for TLE therapeutic intervention.