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Neurobiol Dis. 2017 Jul;103:174-183. doi: 10.1016/j.nbd.2017.04.013. Epub 2017 Apr 19.

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

Author information

1
Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6085, USA; Department of Psychiatry, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine ARC 517, Philadelphia, PA 19104-5127, USA.
2
Department of Psychiatry, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine ARC 517, Philadelphia, PA 19104-5127, USA.
3
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6085, USA.
4
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
5
Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6085, USA; Department of Psychiatry, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine ARC 517, Philadelphia, PA 19104-5127, USA. Electronic address: sande@mail.med.upenn.edu.

Abstract

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.

KEYWORDS:

Hyperactivity; Medium spiny neurons; Motor behavior; Neurodevelopment; Schizophrenia; Striatum; ZSWIM6

PMID:
28433741
PMCID:
PMC5703052
DOI:
10.1016/j.nbd.2017.04.013
[Indexed for MEDLINE]
Free PMC Article

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