Abstract
Reelin is an extracellular matrix protein, which plays a pivotal role in embryonic neuronal migration and development of the laminar structure of cerebral cortex. In the adult brain, Reelin is produced by GABAergic interneurons and plays a role in synaptic plasticity, dendritic morphology, and cognitive function. Binding of the secreted Reelin to its receptors (VLDLR and ApoER2), induces phosphorylation of intracellular adaptor protein Disabled-1, which may be exclusively involved in Reeling signaling in the nervous system. Genetic association studies suggest that REELIN gene is associated with psychiatric disorders including schizophrenia. We have recently found novel pathogenic copy number variations (CNV) in Japanese schizophrenia patients, including deletions at 7q22.1 on which Reelin gene is located. In the present study, we carried out comprehensive behavioral and neurochemical analyses in heterozygous Reelin Orleans mutant (ROM) mice, in which a 220 nucleotide deletion exists in the 3’ region of the Reelin gene, resulting in a frame shift with production of the C-terminal truncated Reelin. ROM is closely related to the CNV discovered in our schizophrenia patient. The mutant mice showed a reduction of natural aversion to illuminated open areas in the open field test, some abnormalities in 3-chambered social interaction test, and impairments in motor coordination and learning in rotarod test. Methamphetamine-induced hyperactivity was significantly reduced in ROM mice compared with WT mice, which was associated with alteration of methamphetamine-induced dopamine release in the nucleus accumbens. Region-specific alterations of GABAergic markers, including GAD67 and GABA-A receptor subunit expression levels were demonstrated in the brains of mutant mice. These results suggest that CNV of Reelin gene may lead to abnormalities in emotion, social interaction and motor learning/flexibility, which could be associated with altered dopaminergic and GABAergic neuronal systems.