Thalamic glutamatergic neurons regulate seizure onset and generalization in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is a common form of epilepsy in adults. The anterior nucleus of the thalamus (ANT) is a potential therapeutic target due to its role in epileptic networks. Using calcium imaging, we show that glutamatergic neurons in the anterodorsal thalamic nucleus (AD), a subarea of the ANT, are activated during hippocampal seizures. Chemogenetic inhibition of AD glutamatergic neurons suppresses seizure onset and generalization in TLE models, whereas activation promotes seizures. Trans-monosynaptic tracing identifies the postsubiculum (PoSub) as an important downstream target of AD. The AD projection terminals in the PoSub exhibit progressively enhanced calcium activity as seizure severity increases. Chemogenetic suppression of AD-PoSub glutamatergic terminals alleviates seizure onset and generalization, whereas activation of this projection exacerbates seizures. In summary, these findings demonstrate that AD glutamatergic neurons modulate TLE through the AD-PoSub circuit, providing insights into circuit-specific therapeutic strategies for epilepsy.