Septo-subicular cholinergic circuit promotes seizure development via astrocytic inflammation

The central dogma explaining epileptic seizures largely revolves around the classic theory of "excitability-inhibition" imbalance between glutamatergic and GABAergic transmission. Cholinergic neurons play a significant role in epilepsy; however, these neuronal populations are molecularly and structurally heterogeneous. Here, we show a subpopulation of subiculum-projecting septal cholinergic neurons that promote seizure development. Functionally, this subpopulation is suppressed during seizures. Selective manipulation of the septo-subicular cholinergic circuit bidirectionally regulates the development of hippocampal seizures. Notably, cholinergic signaling enhances subicular astrocytic caspase-1-mediated neuroinflammation via M3 muscarinic receptors, increasing excitatory synaptic transmission and promoting seizure development. Together, these results demonstrate that activation of the septo-subicular cholinergic circuits facilitates seizure development via astrocytic inflammation. Our findings provide insight into the cholinergic mechanism involved in epilepsy and suggest targeted therapeutic strategies for epilepsy treatment, focusing on the specific cholinergic neuronal subpopulation.