Neuropsychological deficits in mice depleted of the schizophrenia susceptibility gene CSMD1

PLoS One. 2013 Nov 14;8(11):e79501. doi: 10.1371/journal.pone.0079501. eCollection 2013.

Abstract

Recent meta-analyses of schizophrenia genome-wide association studies (GWASs) have identified the CUB and SUSHI multiple domains 1 (CSMD1) gene as a statistically strong risk factor. CSMD1 is a complement control-related protein suggested to inhibit the classical complement pathway, being expressed in developing neurons. However, expression of CSMD1 is largely uncharacterized and relevance for behavioral phenotypes is not previously demonstrated. Here, we assess neuropsychological behaviors of a Csmd1 knockout (KO) mouse in a selection of standard behavioral tests. Deregulation of neuropsychological responses were observed in both the open field and the elevated plus maze tests, in which KO mice spent 55% and 33% less time than WT littermate mice in open areas, respectively. Altered behaviors were also observed in tail suspension and to higher acoustic stimuli, for which Csmd1 KO mice showed helplessness and moderate increase in startle amplitude, respectively. Furthermore, Csmd1 KO mice also displayed increased weight-gain and glucose tolerance, similar to a major phenotype of the metabolic syndrome that also has been associated to the human CSMD1 locus. Consistent with a role in the control of behaviors, Csmd1 was found highly expressed in the central nervous system (CNS), and with some expression in visceral fat and ovary, under tissue-specific control by a novel promoter-associated lncRNA. In summary, disruption of Csmd1 induces behaviors reminiscent of blunted emotional responses, anxiety and depression. These observations suggest an influence of the CSMD1 schizophrenia susceptibility gene on psychopathology and endophenotypes of the negative symptom spectra.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Cerebral Cortex / metabolism
  • Cluster Analysis
  • Female
  • Gene Expression Regulation
  • Gene Order
  • Gene Targeting
  • Genetic Predisposition to Disease*
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Neuropsychological Tests
  • Promoter Regions, Genetic
  • RNA, Long Noncoding / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Transcriptome
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • CSMD1 protein, mouse
  • Membrane Proteins
  • RNA, Long Noncoding
  • RNA, Messenger
  • Tumor Suppressor Proteins

Grant support

This study was supported by the Research Council of Norway (Psykisk Helse Grant No. 186001 and the FUGE Grant Nos. 151904 and 183327), Bergen Medical Research Foundation (BMFS), The Kristian Gerhard Jebsen Foundation, Helse Vest RHF and Dr. Einar Martens Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.