Abstract
Disrupted-in-schizophrenia 1(DISC1) is a promising candidate susceptibility gene for a spectrum of psychiatric illnesses that share cognitive impairments in common, including schizophrenia, bipolar disorder and major depression. Here we report that DISC1 L100P homozygous mutant shows normal anxiety- and depression-like behavior, but impaired object recognition which is prevented by administration of atypical antipsychotic drug clozapine. Ca2+ image analysis reveals suppression of glutamate-evoked elevation of cytoplasmic [Ca2+] in L100P hippocampal slices. L100P mutant slices exhibit decreased excitatory synaptic transmission (sEPSCs and mEPSCs) in dentate gyrus (DG) and impaired long-term potentiation in the CA1 region of the hippocampus. L100P mutation does not alter proteins expression of the excitatory synaptic markers, PSD95 and synapsin-1; neither does it changes dendrites morphology of primary cultured hippocampal neurons. Our findings suggest that the existence of abnormal synaptic transmission and plasticity in hippocampal network may disrupt declarative information processing and contribute to recognition deficits in DISC1 L100P mutant mice.
Highlights
Major neuropsychiatric illnesses such as schizophrenia, bipolar disorder, major depression and autism spectrum disorder are genetically complex but share overlapping symptoms and environmental risk factors, and molecular etiology [1]
We found no effect of genotype on total travel distance, vertical activity, and stereotypic counts
Our analysis showed that the atypical antipsychotic clozapine (0.6 mg/kg dissolved in 10 % DMSO, Tocris), an antagonist of both dopamine and serotonin receptors, prevented the memory deficits of L100P mutants in novel object recognition (NOR, Fig. 2c) and object-place recognition (NPR, Fig. 2d)
Summary
Major neuropsychiatric illnesses such as schizophrenia, bipolar disorder, major depression and autism spectrum disorder are genetically complex but share overlapping symptoms (for example, cognition deficits in learning, memory and attention) and environmental risk factors (for example, influenza, trauma and stress), and molecular etiology [1]. There is broad agreement that studying rare, highly penetrant risk mutations, for example DISC1, in animal models can shed light on the neural integrity of DISC1 and its relevance to neuropsychiatric disorders, and help to decipher gene-environment interactions in those illnesses. Quite a few animal models with DISC1 mutations have reported altered brain morphology, abnormal plasticity, cognitive and affective deficits [4,5,6,7,8,9]. N-ethyl-N-nitrosourea (ENU)-induced inheritable missense point mutations in exon 2 of the mouse DISC1 gene have been of particular interest since Q31L mutant mice showed depression-like behaviors while L100P mutants showed schizophrenia-like phenotypes [4]. DISC1 L100P and Q31L mutant mice have been considered as potential animal models of psychiatric disorders [10,11,12]. Other independent research groups recently reported that no typical schizophrenia-like or depression-
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