Roles of Heat Shock Factor 1 in Neuronal Response to Fetal Environmental Risks and Its Relevance to Brain Disorders

Abstract

Prenatal exposure of the developing brain to various environmental challenges increases susceptibility to late-onset of neuropsychiatric dysfunction; still the underlying mechanisms remain obscure. Here we show that exposure of embryos to a variety of environmental factors such as alcohol, methylmercury and maternal seizure activates HSF1 in cerebral cortical cells. Furthermore, Hsf1 deficiency in the mouse cortex exposed in utero to subthreshold levels of these challenges causes structural abnormalities and increases seizure susceptibility after birth. In addition, we found that human neural progenitor cells differentiated from induced pluripotent stem cells derived from schizophrenia patients show higher variability in the levels of HSF1 activation induced by environmental challenges compared to controls. We propose that HSF1 plays a crucial role in the response of brain cells to prenatal environmental insults and may be a key component in the pathogenesis of late–onset neuropsychiatric disorders.

Loss of Hippocampal Oligodendrocytes Contributes to the Deficit of Contextual Fear Learning in Adult Rats Experiencing Early Bisphenol A Exposure

“…While it is generally recognized that EBE negatively affects brain through interfering with normal development of neurons [8,42], our finding that the OL loss subsequent to EBE accounts for the impaired hippocampal function suggests that the altered OLs represent an alternative route through which EBE has its adversity in the brain and contributes to the development of neuropsychiatric illness. During early development, unlimited exposure to social and environmental risk factors, such as early life stress, has been known to have lasting negative impacts on the brain and precipitates the development of mental illness later in life [43][44][45]. Both neurons and glia cells in the brain were reported to be the sites of the actions of these challenges [46].…”

Detection of vulnerable neurons damaged by environmental insults in utero

“…Experimental paradigms, including the stress intensity/dose, duration, and the time of observation for individual experiments, are described in Results as well as shown in Table 1 (detailed in Table S1). The conditions for prenatal EtOH exposure, in vitro EtOH exposure, and PTZ-induced maternal seizures were previously described (4,34). For in vivo exposure models, each chemical substrate was administered intraperitoneally once or multiple times once daily for the indicated duration to the pregnant mice (prenatal exposure models) or the pups (postnatal exposure models).…”

“…That such a diverse group of risk factors cause similar disorders suggests fundamental cellular mechanisms that exert adverse effects on brain development irrespective of the type of stress (4). Such mechanisms remain poorly understood, partly because of difficulties in distinguishing differentially affected cells in the brain before damage manifests clinically (5-7).…”

“…Activation then triggers the transcription of HSPs and other downstream target genes. More recently, HSF-1 has been identified as a key player in the initial steps of pathological brain development shortly after prenatal exposure to environmental risk factors, some of which have been implicated in the development of late-onset psychiatric disorders (4).…”

A Guide to Generating and Using hiPSC Derived NPCs for the Study of Neurological Diseases

“…We have previously reported that a significant fraction of the gene signature of schizophrenia hiPSC-derived neurons is conserved in schizophrenia hiPSC-derived neural progenitor cells (NPCs), indicating that NPCs may be a useful cell type for studying the molecular pathways contributing to schizophrenia 1 . We and others have reported aberrant migration, increased oxidative stress and reactive oxygen species, sensitivity to sub-threshold environmental stresses and impaired mitochondrial function in schizophrenia hiPSC NPCs 1,[4][5][6] , as well as decreased neuronal connectivity and synaptic function in schizophrenia hiPSC neurons 5,[7][8][9][10] . If the molecular factors contributing to aberrant migration and/or oxidative stress in schizophrenia hiPSC NPCs also underlie the reduced neuronal connectivity in schizophrenia hiPSC-derived neurons, NPCs could be a robust and highly replicative neural population with which to study the mechanisms responsible for disease.…”