Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice.

Autor: Shevelkin AV; 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., Terrillion CE; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Abazyan BN; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Kajstura TJ; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Jouroukhin YA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Rudow GL; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Troncoso JC; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Linden DJ; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Pletnikov MV; 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.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2017 Jul; Vol. 103, pp. 144-153. Date of Electronic Publication: 2017 Apr 06.
DOI: 10.1016/j.nbd.2017.04.008
Abstrakt: 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: 3000-5000μm 3 ) and an increased number of smaller somata PCs (volume: 750-1000μm 3 ) 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 R input or 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.
(Copyright © 2017 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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