Neurobehavioral Abnormalities Relevant to Autism Spectrum Disorders Are Detected in Mice with Selective Expression of Mutant DISC1 in Purkinje Cells of Anterior Cerebellum
Objectives: We sought to analyze the brain and behavioral alterations in this mouse model.
Methods: We evaluated volume of the cerebellum and PC in mice at postnatal (P) day 21 and 150 after assessing behavioral phenotypes in male and female mice in novelty-induced activity, elevated plus maze, Y maze, object and place recognition, fear conditioning and rotarod. Conventional western blotting and electrophysiological technics were used in the experiments. All protocols were approved by the Animal Care and Use Committee at Johns Hopkins University.
Results: We found a significant decrease in PC size at P21 but not at P150. Analysis of soma PC size showed small and big soma PC in the anterior cerebellum of control mice, but only small soma PC size in mutant DISC1 mice at P21. Neither total number of PC nor volume of the cerebellum were significantly altered in mutant DISC1 mice. No up-regulation of cellular markers of inflammation was observed in mutant mice. Mutant male but not female mice demonstrated abnormal social interaction, hyperactivity and deficient novel object recognition. We observed no group differences in elevated plus maze, spontaneous alteration or spatial recognition in Y maze. Preliminary electrophysiological experiments found higher frequency and amplitude of mEPSCs, but no changes in excitability and Rinput of PC in mutant DISC1 mice. Mutant DISC1 mice had comparable expression of NR1 and NR2A but significantly more expression of SNAP-25 and PSD-95 in the cerebellum but not in the cortex.
Conclusions: Our findings indicate that mutant DISC1 affects PC morphology at P21 and produces cognitive and social abnormalities in adult mice. This may have the potential to advance our knowledge of the role of DISC1 in maturation and function of the cerebellum related to neurodevelopmental disorders.