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

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 (DISCI), and DISCI variants have been associated with neurodevelopmental disorders, we evaluated the role of DISCI in cerebellar physiology and associated behaviors using a mouse model of inducible and selective expression of a dominant-negative,C-terminus truncated human DISCI (mutant DISCI) in PCs. Mutant DISCI 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 DISCI was associated with a decreased number of large somata PCs (volume: 3000-5000 pm(3)) and an increased number of smaller somata PCs (volume: 750-1000 mu m(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 DISCI alters the physiology of PCs, possibly leading to abnormal recognition memory in mice. (C) 2017 Elsevier Inc. All rights reserved.