Discussion
This study provides experimental evidence of a series of synaptic alterations of the lateral and the medial perforant paths in response to the transient hypofunction of NMDARs. We documented persistent dysregulation in the glutamate release process from the LPP synapse, blunted induction of LPP LTP, and decreased synaptic filtering capability. In the MPP-DG synapse, the altered glutamate release was accompanied by impaired CB1R-dependent LTD and weakened LTP. Mechanistically, the impairment of MPP LTD was partly due to decreased functional expression of the CB1R. More importantly, enhancing the 2-AG signaling pathway via pharmacological inhibition of the MAGL enzyme restored the strength of the MPP LTD. At the behavioral level, we show for the first time that transient hypofunction of NMDARs impairs spatial discrimination, a cognitive task in which DG plays a critical role.