Hippocampal reelin and GAD67 gene expression and methylation in the GFAP.HMOX1 mouse model of schizophrenia

Schizophrenia is a complex neuropsychiatric disorder featuring enhanced brain oxidative stress and deficient reelin protein. GFAP.HMOX1^0-12m mice that overexpress heme oxygenase-1 (HO-1) in astrocytes manifest a schizophrenia-like neurochemical, neuropathological and behavioral phenotype including brain oxidative stress and reelin downregulation. We used RT-PCR, targeted bisulfite next-generation sequencing, immunohistochemistry and in situ hybridization on hippocampal tissue of GFAP.HMOX1^0-12m mice to delineate a possible molecular mechanism for the downregulation of reelin and to identify the neuronal and non-neuronal (glial) cell types expressing reelin in our model. We found reduced reelin and increased DNMT1 and TET1 mRNA expression in the hippocampus of male GFAP.HMOX1^0-12m mice and reduced GAD67 mRNA expression in females. These mRNA changes were accompanied by sexually dimorphic alterations in DNA methylation levels of Reln and Gad1 genes. Reelin protein was expressed by oligodendrocytes and GABAergic interneurons, but not by astrocytes or microglia in GFAP.HMOX1^0-12m and wild-type brains of both sexes. Reelin mRNA was also observed in oligodendrocytes. Moreover, a significant downregulation of reelin-expressing oligodendrocytes was detected in the hippocampal dentate gyrus of male GFAP.HMOX1^0-12m mice. These results suggest a novel mechanism for brain reelin depletion in schizophrenia. Containment of the astrocytic HO-1 cascade by pharmacological or other means may protect against stress-induced brain reelin depletion in schizophrenia and other neurodevelopmental disorders.