Abstract
Schizophrenia is a debilitating psychotic disorder that affects up to 1.5% of the population worldwide. Two recent studies in humans identified genome-wide significant associations between schizophrenia and single-nucleotide polymorphisms (SNPs) in an intron of CSMD1. The effect of deleting CSMD1 on mouse behavior is unknown. The present study utilized mice with a mutant Csmd1 allele in which the first exon had been ablated (KO mice). All Csmd1 transcripts that included the first exon were absent in the brains of KO mice, but there was persistent expression of at least one other transcript that does not include the first exon. Wild type (WT), heterozygous (HET), and KO mice were assessed using several well-established behavioral paradigms that model aspects of schizophrenia. Csmd1 KO mice did not differ from wild-type littermates for sensorimotor gating (measured as prepulse inhibition), social interaction, anhedonia (measured by sucrose preference), or sensitivity to the locomotor stimulant effects of the dopaminergic agent d-amphetamine. These data demonstrate that loss of Csmd1 transcripts that include the first exon does not alter multiple well-established behaviors that model aspects of schizophrenia. The SNP most strongly associated with schizophrenia in humans is between exons 3 and 4; therefore, ablation of exon 1 appeared to be a logical animal model. Nevertheless, future studies should consider alternative mouse models including gain-of-function mutations, and loss-of-function mutations that target alternative transcripts of Csmd1.
Highlights
IntroductionSchizophrenia is a psychotic disorder characterized by positive symptoms (delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior) and negative symptoms (flattened affect, paucity of speech, and reduced motivation) [1]
Schizophrenia is a psychotic disorder characterized by positive symptoms and negative symptoms [1]
KO mice express less than 30% of normal Csmd1 levels in the brain, all of which appears to come from Csmd1-4
Summary
Schizophrenia is a psychotic disorder characterized by positive symptoms (delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior) and negative symptoms (flattened affect, paucity of speech, and reduced motivation) [1]. These debilitating features contribute to profound social and/or occupational dysfunction [1]. The exact etiology of schizophrenia is unknown, but human studies have demonstrated significant brain abnormalities, including decreased brain volume, reduced activity of the frontal and temporal lobes, and aberrant neural connectivity [2]. Initial support for the dopaminergic hypothesis of schizophrenia came from evidence that drugs that decrease dopaminergic activity reduce psychotic symptoms, while drugs that increase dopaminergic activity produce psychosis [2]. Dopaminergic dysfunction in schizophrenic patients has been controversial, there may be an increase in D2 receptor density and alterations in dopamine synthesis and release [2]
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