Behavioral dysregulation
Our spatial discrimination tests suggest that transient hypofunction of NMDARs alters the functional integrity of the DG and thus pattern separation activity, a model of neuronal activity that enables the recognition of independent events despite highly similar information content (Yassa and Stark, 2011). Previous studies have documented reduced volume and alterations in the cellular architecture of the hippocampus and surrounding areas of schizophrenic individuals, with the greatest volume loss in the DG (Nakahara et al., 2019). Volumetric dysregulation also implies changes in the information processing in which DG participates, including pattern separation activity (Faghihi and Moustafa, 2015). In line with this, a recent study has shown deficits in mnemonic discrimination in schizotypal and first-episode psychotic individuals (Kraguljac et al., 2021). We demonstrate for the first time that transient hypofunction of NMDARs impairs spatial discrimination in juvenile male rats. This finding substantiates the idea that impaired mnemonic discrimination is present during the early or prodromal phase of schizophrenia. Consistent with this, recent work showed that children and adolescents at high risk of developing schizophrenia exhibited impaired mnemonic discrimination compared to a control group (İmamoğlu et al., 2023). Given the similar impairments in the mnemonic discrimination task found in our animal model and individuals at high risk for developing schizophrenia, we propose that mnemonic discrimination can be used as a clinical hallmark of the cognitive status of individuals with a high risk of developing schizophrenia. Early screening could allow early therapeutic interventions and modify the course of the illness, as previously suggested (Insel, 2010). At the preclinical level, the animal models that presumably mimic the phenotype schizophrenia should reproduce this impaired mnemonic discrimination in the juvenile stage of animals.