Abstract
Understanding gene-environment interactions in the pathogenesis of schizophrenia remains a major research challenge. Matrix metalloproteinase-9 (MMP-9) has been previously implicated in the pathophysiology of schizophrenia. In the present study, adolescent Mmp-9 heterozygous mice, with a genetically lower level of MMP-9, were subjected to resident-intruder psychosocial stress for 3 weeks and then examined in behavioral tests that evaluated cognitive deficits and positive- and negative-like symptoms of schizophrenia. Cognitive and positive symptoms in unstressed Mmp-9 heterozygous mice were unaffected by stress exposure, whereas negative symptoms were manifested only after stress exposure. Interestingly, negative symptoms were ameliorated by treatment with the antipsychotic drug clozapine. We describe a novel gene × environment interaction mouse model of schizophrenia. Lower MMP-9 levels in the brain might be a risk factor for schizophrenia that, in combination with environmental factors (e.g., psychosocial stress), may evoke schizophrenia-like symptoms that are sensitive to antipsychotic treatment.
Highlights
Schizophrenia is a neuropsychiatric disorder that affects approximately 0.5% of the human population (Saha et al, 2005)
The present study investigated the effects of low matrix metalloproteinase-9 (MMP-9) activity on the predisposition to schizophrenia-like symptoms in mice that were subjected to psychosocial stress
The present study found that psychosocial stress that was induced in the resident-intruder paradigm and low levels of MMP-9 were collectively required to evoke negative-like symptoms of schizophrenia in mice, indicated by: (i) an increase in immobility in the tail suspension test, reflecting by a decrease in the ability of stressed heterozygous mice to cope with the adverse conditions; and (ii) a shorter interaction time with a gender-matched conspecific mouse, reflecting social withdrawal
Summary
Schizophrenia is a neuropsychiatric disorder that affects approximately 0.5% of the human population (Saha et al, 2005). Multiple genes have been implicated in the etiology of schizophrenia (McGuffin et al, 2003; Hosak, 2013), no single genetic alteration has been able to satisfactorily explain all of its complex symptoms (Gottesman and Shields, 1967; Sanders et al, 2008). MMP-9 has been shown to be involved in N-methyl-D-aspartate (NMDA) signaling and functional and structural synaptic plasticity (Huntley, 2012; Vafadari et al, 2016). These phenomena have been implicated in MMP-9 and Schizophrenia the pathophysiology of schizophrenia (Olney et al, 1999; Anand et al, 2000; du Bois and Huang, 2007; Penzes et al, 2011; Moyer et al, 2015). Mmp-9 knockout mice have been shown to exhibit alterations of emotional and cognitive behaviors (Mizoguchi et al, 2010)
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