Corticosterone treatment during adolescence induces down-regulation of reelin and NMDA receptor subunit GLUN2C expression only in male mice: implications for schizophrenia

Stress exposure during adolescence/early adulthood has been shown to increase the risk for psychiatric disorders such as schizophrenia. Reelin plays an essential role in brain development and its levels are decreased in schizophrenia. However, the relationship between stress exposure and reelin expression remains unclear. We therefore treated adolescent reelin heteroyzogous mice (HRM) and wild-type (WT) littermates with the stress hormone, corticosterone (CORT) in their drinking water (25 mg/l) for 3 wk. In adulthood, we measured levels of full-length (FL) reelin and the N-R6 and N-R2 cleavage fragments in the frontal cortex (FC) and dorsal (DH) and ventral (VH) hippocampus. As expected, levels of all reelin forms were approximately 50% lower in HRMs compared to WT. In male mice, CORT treatment significantly decreased FL and N-R2 expression in the FC and N-R2 and N-R6 levels in the DH. This reelin down-regulation was accompanied by significant reductions in downstream N-methyl-D-aspartate (NMDA) GluN2C subunit levels. There were no effects of CORT treatment in the VH of either of the sexes and only subtle changes in female DH. CORT-induced reelin and GluN2C down-regulation in males was not associated with changes in two GABAergic neuron markers, GAD67 and parvalbumin, or glucocorticoids receptors (GR). These results show that CORT treatment causes long-lasting and selective reductions of reelin form levels in male FC and DH accompanied by changes in NMDAR subunit composition. This sex-specific reelin down-regulation in regions implicated in schizophrenia could be involved in the effects of stress in this disease.