Neurobehavioral Abnormalities Relevant to Autism Spectrum Disorders Are Detected in Mice with Selective Expression of Mutant DISC1 in Purkinje Cells of Anterior Cerebellum

Friday, May 13, 2016: 11:30 AM-1:30 PM
Hall A (Baltimore Convention Center)
A. V. Shevelkin1,2, B. N. Abazyan1, C. Yang1, O. A. Mychko1, G. L. Rudow3, J. C. Troncoso3 and M. V. Pletnikov1,4, (1)Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, (2)P.K.Anokhin Institute of Normal Physiology, Moscow, Russia, (3)Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, (4)Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD
Background:  Disrupted-In-Schizophrenia-1(DISC1) and its variants have been associated with neurodevelopmental disorders, including schizophrenia and autism spectrum disorders (ASD). Purkinje cells (PC) express DISC1. We generated a mouse model of inducible and selective expression of mutant DISC1 in PC of anterior lobuli of the cerebellum (II-V and internal side of VI).

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.

See more of: Animal Models
See more of: Animal Models