Psychosocial Stress Induces Schizophrenia-Like Behavior in Mice With Reduced MMP-9 Activity

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.

Long-term Hippocampal and Amydalar Dendritic Spine Alterations after Adolescence Psychosocial Stress

“…Present world scenario places a large population of adolescent individuals (10-20%) at risk, particularly in the developing world, with most being underdiagnosed and under-treated leading to growing cases of depression and suicide (Kessler et al 2007). In our previous work (Vafadari and Mitra et al 2019) we had reported that wild-type mice that underwent adolescence psychosocial stress exhibited increased locomotion in open field and after treatment with MK-801 providing evidence for behavioral implications of the stress paradigm. We had further shown that reduced levels of synaptic, extracellularly-operating matrix metalloproteinase-9 (MMP-9) known to affect dendritic spine morphology (Michaluk et al, 2011), further accentuates the phenotype and leads to schizophrenia like symptoms (Vafadari and Mitra et al 2019).…”

“…In our previous work (Vafadari and Mitra et al 2019) we had reported that wild-type mice that underwent adolescence psychosocial stress exhibited increased locomotion in open field and after treatment with MK-801 providing evidence for behavioral implications of the stress paradigm. We had further shown that reduced levels of synaptic, extracellularly-operating matrix metalloproteinase-9 (MMP-9) known to affect dendritic spine morphology (Michaluk et al, 2011), further accentuates the phenotype and leads to schizophrenia like symptoms (Vafadari and Mitra et al 2019). Hence, we investigated whether there are any long-term structural changes in wild-type mice due to stress that might have acted as a pre-cursor to the behavioral changes and gene x environment (GXE) affects.…”

“…For the second group, mice were introduced into the cages of gender matched FVB mice (aggressive strain, 3 months old). The detailed protocol of stressing is already explained (Vafadari et al 2019). Briefly, the experimental mice are exposed to the FVB mice till the first attack on day1.…”

Stress and the Role of the Gut–Brain Axis in the Pathogenesis of Schizophrenia: A Literature Review

“…Our knowledge in the basic and clinical pathophysiology of neuropsychiatric diseases, such as schizophrenia, is still limited. “Schizophrenia is a severe neuropsychiatric disease that is characterized by impairments in perception, cognition, and avolition, leading to positive, cognitive, and negative symptoms, respectively” [ 3 ]. The etiology of schizophrenia remains unknown [ 4 ].…”

“…Another important factor is stress. Stress can induce changes in the gut microbiome [ 7 ] and it is well known that stress is one of the risk factors for the pathogenesis of schizophrenia [ 3 , 8 , 9 , 10 , 11 ]. Finally, several lines of evidence support the notion that gut microbiota can affect stress-related behaviors [ 12 ].…”