Environmental adversity, endoplasmic reticulum stress, and neurogenesis

Abstract

Environmental adversity experienced during the prenatal period can include maternal nutritional deficiency, infectious agents, heavy metals, industrial chemicals, air pollution, medication, alcohol exposure, and substance use, as well as maternal factors such as diabetes. If these adversities occur during certain developmental time windows, they can significantly impact fetal development and have long-lasting neurobehavioral deficits. However, molecular mechanisms underlying the impact of environmental adversity remains unclear. The process by which new neurons form in the brain is neurogenesis. In certain brain regions neurogenesis continues throughout the lifespan and is essential for continued neurodevelopment and good mental health. Appropriate cellular responses to both extrinsic and intrinsic stressors require maintenance of the proteome, which relies on homeostasis of the endoplasmic reticulum (ER). Perturbations of ER homeostasis, such as the depletion of nutrients and disturbances in calcium or redox status, lead to abnormal accumulation of misfolded proteins and induce ER stress, which is monitored by the unfolded protein response (UPR). UPR is an adaptive reaction that restores protein homeostasis or triggers apoptotic cell death. Recent research indicates that ER stress during development can impair neurogenesis. We hypothesize that ER stress-mediated disruption of neurogenesis underlies the neurobehavioral deficits caused by environmental adversity. In this review, we discuss evidence of the impact that environmental adversities have on neurogenesis and the involvement of ER stress. We also discuss crosstalk across ER stress, oxidative stress, autophagy, and neuroinflammation, as well as potential therapeutic strategies that target ER stress/UPR for the treatment of neurobehavioral deficits associated with environmental adversities.

Keywords: Brain development; differentiation; neural stem cells; neurodevelopmental disorder; substance abuse; unfolded protein response.