Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia

Abstract

Schizophrenia etiology is thought to involve an interaction between genetic and environmental factors during postnatal brain development. However, there is a fundamental gap in our understanding of the molecular mechanisms by which environmental factors interact with genetic susceptibility to trigger symptom onset and disease progression. In this review, we summarize the most recent findings implicating oxidative stress as one mechanism by which environmental insults, especially early life social stress, impact the development of schizophrenia. Based on a review of the literature and the results of our own animal model, we suggest that environmental stressors such as social isolation render parvalbumin-positive interneurons (PVIs) vulnerable to oxidative stress. We previously reported that social isolation stress exacerbates many of the schizophrenia-like phenotypes seen in a conditional genetic mouse model in which NMDA receptors (NMDARs) are selectively ablated in half of cortical and hippocampal interneurons during early postnatal development (Belforte et al., 2010). We have since revealed that this social isolation-induced effect is caused by impairments in the antioxidant defense capacity in the PVIs in which NMDARs are ablated. We propose that this effect is mediated by the down-regulation of PGC-1α, a master regulator of mitochondrial energy metabolism and anti-oxidant defense, following the deletion of NMDARs (Jiang et al., 2013). Other potential molecular mechanisms underlying redox dysfunction upon gene and environmental interaction will be discussed, with a focus on the unique properties of PVIs.

DOI: 10.3389/fnbeh.2013.00116

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@inproceedings{Jiang2013ConvergenceOG, title={Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia}, author={Zhi-Hong Jiang and Rita M Cowell and Kazu Nakazawa}, booktitle={Front. Behav. Neurosci.}, year={2013} }