Neuropsychological deficits in mice depleted of the schizophrenia susceptibility gene CSMD1.
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.
Dr E. Martens Research Group for Biological Psychiatry and K.G. Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway ; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
Vidar M
VM
Steen
Chirag
C
Nepal
Kari M
KM
Ersland
Rita
R
Holdhus
Marianne
M
Nævdal
Siri M
SM
Ratvik
Silje
S
Skrede
Bjarte
B
Håvik
D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism; D016000:Cluster Analysis; D005260:Female; D005786:Gene Expression Regulation; D023061:Gene Order; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009483:Neuropsychological Tests; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
C581687:CSMD1 protein, mouse; D008565:Membrane Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins