title: Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice.
abstract: In addition to motor function, the cerebellum has been implicated in cognitive and social behaviors. Various structural and functional abnormalities of Purkinje cells (PCs) have been observed in schizophrenia and autism. As PCs express the gene Disrupted-In-Schizophrenia-1 (DISC1), and DISC1 variants have been associated with neurodevelopmental disorders, we evaluated the role of DISC1 in cerebellar physiology and associated behaviors using a mouse model of inducible and selective expression of a dominant-negative, C-terminus truncated human DISC1 (mutant DISC1) in PCs. Mutant DISC1 male mice demonstrated impaired social and novel placement recognition. No group differences were found in novelty-induced hyperactivity, elevated plus maze test, spontaneous alternation, spatial recognition in Y maze, sociability or accelerated rotarod. Expression of mutant DISC1 was associated with a decreased number of large somata PCs (volume: 3000-5000μm3) and an increased number of smaller somata PCs (volume: 750-1000μm3) without affecting the total number of PCs or the volume of the cerebellum. Compared to control mice, attached loose patch recordings of PCs in mutant DISC1 mice revealed increased spontaneous firing of PCs; and whole cell recordings showed increased amplitude and frequency of mEPSCs without significant changes in either Rinputor parallel fiber EPSC paired-pulse ratio. Our findings indicate that mutant DISC1 alters the physiology of PCs, possibly leading to abnormal recognition memory in mice.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; P.K. Anokhin Research Institute of Normal Physiology, Moscow, Russian Federation.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Shevelkin
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Chantelle E
authors.initials: CE
authors.lastname: Terrillion
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Bagrat N
authors.initials: BN
authors.lastname: Abazyan
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Tymoteusz J
authors.initials: TJ
authors.lastname: Kajstura
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Yan A
authors.initials: YA
authors.lastname: Jouroukhin
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Gay L
authors.initials: GL
authors.lastname: Rudow
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Linden
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: mpletnik@jhmi.edu.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pletnikov
mesh_terms: D000818:Animals; D060825:Cognitive Dysfunction / Q000235:genetics / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D005260:Female; D006801:Humans; D008124:Locomotion / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D011689:Purkinje Cells / Q000378:metabolism*; D012919:Social Behavior
chemical_list: C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins
keywords: Autism; Cerebellum; DISC1; Purkinje cells; Schizophrenia