Loss of the neurodevelopmental gene Zswim6 alters striatal morphology and motor regulation

NEUROBIOLOGY OF DISEASE

卷:103

Article

Tischfield, David J.^1,2  Saraswat, Dave K.²  Furash, Andrew³  Fowler, Stephen C.⁴  Fuccillo, Marc V.³  Anderson, Stewart A.^1,2 

[1] Univ Penn, Perelman Sch Med, Neurosci Grad Grp, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Psychiat, ARC 517, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA

[4] Univ Kansas, Dept Pharmacol & Toxicol, Lawrence, KS 66045 USA

关键词: ZSWIM6;    Striatum;    Schizophrenia;    Medium spiny neurons;    Hyperactivity;    Motor behavior;    Neurodevelopment;   

DOI  :  10.1016/j.nbd.2017.04.013

来源: Elsevier

【 摘 要 】

The zinc-finger SWIM domain-containing protein 6 (ZSWIM6) is a protein of unknown function that has been associated with schizophrenia and limited educational attainment by three independent genome-wide association studies. Additionally, a putatively causal point mutation in ZSWIM6 has been identified in several cases of acromelic frontonasal dysostosis with severe intellectual disability. Despite the growing number of studies implicating ZSWIM6 as an important regulator of brain development, its role in this process has never been examined. Here, we report the generation of Zswim6 knockout mice and provide a detailed anatomical and behavioral characterization of the resulting phenotype. We show that Zswim6 is initially expressed widely during embryonic brain development but becomes restricted to the striatum postnatally. Loss of Zswim6 causes a reduction in striatal volume and changes in medium spiny neuron morphology. These changes are associated with alterations in motor control, including hyperactivity, impaired rotarod performance, repetitive movements, and behavioral hyperresponsiveness to amphetamine. Together, our results show that Zswim6 is indispensable to normal brain function and support the notion that Zswim6 might serve as an important contributor to the pathogenesis of schizophrenia and other neurodevelopmental disorders. (C) 2017 Elsevier Inc. All rights reserved.

【 授权许可】

Free