L'expression d'une mutation DISC1 dans les cellules de Purkinje augmente leur activité spontanée et affecte les comportements cognitifs et sociaux chez la souris

Aperçu: G.M.

En plus de la fonction motrice, le cervelet a été impliqué dans les comportements cognitifs et sociaux. Diverses anomalies structurelles et fonctionnelles des cellules de Purkinje (PC) ont été observées dans la schizophrénie et l'autisme.

Les résultats indiquent que le DISC1 mutant modifie la physiologie des PC, ce qui peut conduire à une mémoire de reconnaissance anormale chez la souris.

Neurobiol Dis. 2017 Apr 6. pii: S0969-9961(17)30082-7. doi: 10.1016/j.nbd.2017.04.008.

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

Shevelkin AV¹, Terrillion CE², Abazyan BN², Kajstura TJ³, Jouroukhin YA², Rudow GL⁴, Troncoso JC⁴, Linden DJ³, Pletnikov MV⁵.

Author information

1

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.

2

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

3

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

4

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

5

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

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 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. Published by Elsevier Inc.

PMID: 28392471

DOI: 10.1016/j.nbd.2017.04.008