Neonatal hypofunction of NMDA receptors alters perforant path synaptic plasticity, filtering and impairs dentate gyrus-mediated spatial discrimination

Background: and Purpose: Transient hypofunction of NMDARs represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant path synapses, have barely been explored in this pathological condition. Experimental Approach: We identified a series of synaptic alterations of the lateral and medial perforant paths, in animals neonatally treated with the NMDAR antagonist MK-801. The dysregulation here reported suggests decreased cognitive performance, for which the dentate gyrus is critical. Key Results: We identified alterations in the synaptic properties of the lateral and medial perforant paths to the dentate gyrus synapses in MK-801-treated animals. Altered glutamate release and decreased synaptic strength precede an impairment in the induction and expression of LTP and cannabinoid 1 receptor (CB1R)-mediated LTD. Remarkably, by inhibiting the degradation of 2-arachidonoylglycerol, the endogenous ligand of the CB1R, we restored the LTD in animals treated with MK-801. Additionally, we show for the first time that spatial discrimination, a cognitive task that requires dentate gyrus integrity, is impaired in animals exposed to transient hypofunction of NMDARs. Conclusion and Implications: Descriptive and mechanistic evidence showing the dysregulation of glutamatergic transmission and synaptic plasticity from the entorhinal cortex to the dentate gyrus is presented. These findings may explain the cellular dysregulations underlying the altered cognitive processing in the dentate gyrus associated with schizophrenia.