Zona incerta somatostatin+ neurons modulate seizure progression through hypothalamic circuits

Abstract GABAergic neurons critically regulate epileptic seizures, yet circuit mechanisms mediated by subtype-specific GABAergic neurons in the zona incerta (ZI) remain unclear. Here we reveal the essential role of ZI somatostatin + GABAergic neurons in seizure modulation in the mouse hippocampal kindling model. In vivo Ca 2+ fiber photometry and optogenetics show that ZI GABAergic neurons are gradually activated during seizure progression. Opto-activation inhibits seizure progression, especially the spread of generalized seizures at the later phase, whereas opto-inhibition accelerates it. Although both somatostatin + and parvalbumin + neurons are dynamically recruited during seizure progression, only somatostatin + neurons exert bidirectional seizure modulation. Circuitry mapping and functional modulation demonstrate that ZI somatostatin + neurons projecting to the ventromedial hypothalamus (VMH) glutamatergic neurons suppress the spread of generalized seizures by inhibiting the excitability of VMH-related downstream seizure-spread regions. These findings uncover a cell-type-specific circuit mechanism for seizure regulation by ZI somatostatin + neurons, highlighting these neurons as a potential therapeutic target for epilepsy.