Objective Over 30% of people with epilepsy are not responsive to the treatment even to the best available medications.Therefore, it is of great theoretical and clinical significance to investigate the mechanisms underlying epilepsy, and to search for effective therapies.Previous reports have shown that N-methyl-D-aspartate (NMDA) receptors are extensively involved in epilepsy genesis and recurrence.However, few studies have focused on the role of extrasynaptic NMDA receptors in epileptogenesis.Therefore, in the present study we analyzed extrasynaptic NMDA receptor-mediated currents during the early stage of epileptogenesis.NAD+ is a fundamental molecule in cells, which has been shown to decrease oxidative and excitotoxic cell death as well as ischemic brain injury.In the current study, therefore, we also tested the effect of NAD+ on pilocarpine-induced epilepsy.Methods Adult C57BL/6 mice models of pilocarpine-induced epilepsy were established, and hippocampal slices were prepared at 24 h after the onset of status epilepticus (SE).Changes in synaptic and extrasynaptic NMDA receptor-mediated excitatory post-synaptic currents (NMDA-EPSCs) were recorded in CA1 pyramidal neurons by whole-cell patch clamp technique.On the other hand, NAD+ or vehicle was i.p.injected 1 h after the onset of pilocarpine-induced SE.Induction of spontaneous recurrent seizures (SRS) was recorded by EEG recording technique in freely moving mice at two weeks later.Results (1) There were no significant differences in synaptie NMDA-EPSCs between pilocarpine and control groups in terms of rise time and decay time.(2) The peak amplitudes and rise time of extrasynaptic NMDA-EPSCs were not statistically different between the two groups.(3) Extrasynaptic NMDA-EPSCs decay was significantly faster in the pilocarpine-treated mice.(4) NAD+ treatment markedly decreases the number of spontaneous epileptiform EEG activity.(5) Histological experiments showed that NAD+ treatment reduces the brain injury in the pilocarpine-induced epilepsy model mice.Conclusion (1) Extrasynaptic NMDA receptors may participate in early-stage of epileptogenesis.(2) Our study indicated a therapeutic potential ofNAD+ for epilepsy.