1 Complex Roles of Notch Signaling in the Development of Temporal Lobe Epilepsy: Evidence and Speculation

The Notch pathway is well known as a master regulator of neural stem cells, but accumulating evidence suggest both novel and sophisticated roles for Notch signaling in adult brain. In the postnatal hippocampus, the regulatory function of Notch signaling on synaptic plasticity has been studied extensively. Mice with germline deletion of Notch1 or presenilins exhibited impaired long-term potentiation (LTP) and working memory, which could be understood as a consequence of disruptions in Notch-dependent neurite development and neuronal migration. Compared with long-term synaptic plasticity, recent studies have shown that Notch pathway is induced instantly by neuronal activity, suggesting a correlate of stimulus-dependent Notch activity and synaptic transmission. However, the role of those non-canonical functions of Notch signaling in neurological disorders has not been characterized so far. More recently, we have reported that Notch signaling activation led to an increase in epileptiform discharges in a mouse model of acute seizures. Temporal lobe epilepsy (TLE) is among the most frequent types of drug-resistant epilepsy, and the reorganization of neural circuits underlying the generation of recurrent seizures has been demonstrated, including impaired long-term potentiation of synaptic networks and disordered short-term synaptic responses. Here, focusing on the primary and new-emerging functions of Notch signaling, we review the complicated roles of Notch in the development of TLE and speculate some potential neuropathogenic mechanisms