Gene–environment interaction of reelin and stress in cognitive behaviours in mice: Implications for schizophrenia

• We tested effects of a ‘two hit’ combination of reelin deficiency and stress in mice.
• Corticosterone induced spatial memory deficits in reelin mutant mice but not controls.
• Corticosterone induced PPI deficits in male controls, but not reelin mutant mice.
• Reelin expression was increased in the PFC of female CORT-treated reelin mice.
• Findings important for understanding of reelin–stress interactions in schizophrenia.

Cognitive deficits are a particularly debilitating symptom group in schizophrenia. We investigated the effect of a ‘two hit’ combination of two factors implicated in schizophrenia development, reelin deficiency and stress, on cognitive behaviours in mice.Male and female heterozygous reelin mice (HRM) and wild-type (WT) controls received the stress hormone, corticosterone (CORT), during early adulthood to simulate chronic stress. The Y-maze, novel object recognition task (NORT), social interaction task and prepulse inhibition (PPI) were used to assess short-term spatial memory, visual non-spatial memory, social recognition memory and sensory gating, respectively. Reelin protein expression was measured in the prefrontal cortex (PFC) and hippocampus.CORT induced spatial memory deficits in male and female HRM but not in WT controls suggesting increased vulnerability of HRM to the effects of stress on cognition. By contrast, CORT disrupted PPI only in male WT mice, but not in male HRM, suggesting a protective role of reelin deficiency against effects of stress on PPI. Male HRM performed worse in the social recognition memory task compared to wild-type controls, irrespective of CORT treatment. No differences were detected in the NORT. Reelin protein expression was increased in the PFC of female CORT-treated HRM but there were no group differences in the hippocampus. Overall, these findings extend our understanding of the role of reelin–stress interactions in schizophrenia.