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.