Role Of Adult-born Dentate Granule Cells In Temporal Lobe Epilepsy And Its Underlying Mechanisms

Epilepsy is a diverse group of neurological disorders that share the central feature of abnormality in terms of neuronal networks and clinical recurrent seizures.Different types of anti-epileptic drugs（AEDs）have been invented to control epileptic seizures;however,one third of the patients still do not respond to a variety of AEDs and become drug-resistant.Temporal lobe epilepsy（TLE）is the most common form of refractory epilepsy and its refractory ratio is up to 75%.Thus,it is urgent to investigate the pathological mechanisms underlying TLE and find new treatment approaches.Meanwhile,TLE is often accompanied with several pathological changes in hippocampus,including abnormal adult neurogenesis.Emerging evidence has suggested that epileptogenic insults may lead to abnormal adult neurogenesis;However,it remains unclear how these adult-born dentate granule cells（abDGCs）contribute to onset of TLE.In the present study,taking advantage of mouse TLE models,we used optogenetics,retrovirus,fiber photometry of calcium signals,pharmacological approaches,as well as electrophysiology to investigate the function of abDGCs generated at different stages relative to epileptogenic insults.First of all,we administered systemic BrdU to label mitotically active cells at different time points and found that kindling had stimulating effects on the proliferation of abDGCs in the SGZ:a substantial increase in mitotic activity was observed at 3 d and 7 d after kindling compared with controls and returned to baseline levels by 14 d.Then,we assessed the functional role of abDGCs during epileptic seizures using Ca²⁺fiber photometry.Calcium signals showed that the abDGCs generated at 3d（acute phase）after mice being fully kindled were functionally inhibited during kindling-induced recurrent seizures.Furthermore,taking advantage of optogenetic tools to selectively manipulate abDGCs bidirectionally,we found that optogenetic activation of abDGCs generated at acute phase after kindled seizures significantly extended,while inhibition curtailed,the seizure duration,without affecting seizure stage and latency to generalized seizures（GS）.Interestingly,we found that the seizure-modulating effect was attributed to specific abDGCs born at a critical acute phase after initial epileptogenic insult.Selectively modulating the abDGCs born at other stages（1 week before or 3 weeks after kindled seizures）exerted no effect on following recurrent seizures.Subsequently,using in vivo electrophysiology combined with optogenitics,we found that selectively activating abDGCs generated at acute phase activated neighboring excitatory early-born dentate granule cells（ebDGCs）.Meanwhile,using pharmacological bloackades to block the glutamatergic neurotransmission or chemogenetic silencing of ebDGCs,we reversed the pro-seizure effect of abDGCs,which indicated that ebDGCs were downstream neural basis that was necessary for pro-seizure effect of abDGCs.On the other hand,repeated inhibition of abDGCs easily produced long-term anti-seizure effect in both kindling and kainic acid（KA）-induced TLE models,which might result from a change of synaptic plasticity.Taken together,we demonstrated that abDGCs generated at a critical period maintains seizure duration via local abnormal recurrent excitatory circuits,and inactivation of these abnormal circuits can long-termly alleviate severity of epileptic seizures.This provides a better understanding of the pathological changes for the precise spatiotemporal control of epilepsy.