White matter protection by inhibitors of glial scar formation in perinatal hypoxia ischemia

Oregon Health & Science University, Portland OR

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Abstract

Summary By adulthood, survivors of premature birth are at significantly increased risk for several forms of severe mental illness, including nonaffective psychosis, schizophrenia, major depressive disorder, and bipolar affective disorder. This preclinical research proposal seeks to define the role of sex-dependent factors that influence early life Extra Cellular Matrix (ECM)-mediated mechanisms that contribute to risks for mental illness in survivors of premature birth as they mature to adulthood. Our proposal thus aligns with strategic goals 1.1. and 1.4 of the 2019-2023 Trans-NIH Strategic Plan for Women's Health Research. We propose to define basic biological differences between male and female neonates that influence mechanisms relevant to enhanced risks for life-long mental illness in preterm survivors. During preterm neonatal brain development, we have found that the hyaluronic acid (HA) backbone of the ECM undergoes remodeling by the enzyme TSG-6 (TNF stimulated gene-6), which displays peak activity. Our preliminary studies support that remodeling of ECM HA by TSG-6 regulates transcriptional maturation of astrocytes which are integral to neuronal function. In knock out mice that lack TSG-6 activity, adults display alterations in anxiogenic and sensorimotor behaviors in a sex-dependent fashion. We have further identified that TSG-6-/- mice display disrupted expression of key regulators of glutamatergic signaling, which we propose are integral to the developmental maturation of neural circuitry underlying these neurobehavioral disturbances. We hypothesize that TSG-6-mediated remodeling of HA in the neonatal brain influences sex-dependent maturation of metabotropic glutamate receptors, glutamate transporters and synaptic spines, which regulate neurotransmission. This proposal will allow us to increase sample size of both males and females to increase statistical power to analyze for sex differences. We will determine key mechanisms by which TSG-6-mediated remodeling of HA in the neonatal brain influences sex- dependent maturation of glutamate receptors, transporters and synaptic spines, which regulate neurotransmission. In aim 1, we will determine whether abnormal expression of glutamatergic signaling regulators in TSG-6-/- brains is sex- and age-dependent. We will analyze the sex- and age-dependent expression of metabotropic glutamate receptors and glutamate transporters including GLT-1, which our preliminary studies found to be dysregulated in TSG-6 null brains. In aim 2, we will determine whether reduction in soma size of TSG-6-/- cortical pyramidal neurons is accompanied by sex-dependent changes in dendritic arborization and spine density in adults. These studies will facilitate our long-term objective to define key cellular and molecular modifications regulated by ECM HA remodeling that influence neuron-astrocyte homeostasis and behavioral outcomes. Our TSG-6-/- animals provide a novel model to address significant gaps in our mechanistic understanding of the sex-dependent regulation of neuronal maturation at critical windows in early brain development that appear to influence later neurobehavioral phenotypes and risk for mental illness in adults.