Hsiao-Tuan Chao - US grants

[unreadable] DESCRIPTION (provided by applicant): MeCP2 is a transcriptional repressor critical for normal neurological function. Rett syndrome (RTT) is a progressive neurodevelopmental disease caused by predominantly loss of function mutations in the X-linked gene encoding the transcriptional repressor, methyl-CpG-binding protein 2 (MECP2) genes. Classic RTT patients exhibit a spectrum of neurological phenotypes that include tremors, ataxia, seizures, stereotypes, anxiety, mental retardation, breathing dysrhythmias, and loss of motor skills and language. Recent reports reveal that overexpression of MeCP2 is also detrimental to neurological function and is a frequent cause of mental retardation and progressive neurological symptoms in males. I hypothesize that misregulation of MeCP2 levels results in abnormal excitatory and inhibitory neuronal activity, which leads to the spectrum of neurological phenotypes. In order to test this hypothesis, I will examine the neurophysiological properties of neurons upon loss or doubling of MeCP2 develop and characterize conditional Mecp2 knockout mouse models specific to excitatory and inhibitory neurons, and assess their behavioral and neurophysiological phenotypes. PUBLIC HEALTH RELEVANCE: The research proposal seeks to understand the impact of altered MeCP2 levels on neuronal function and to identify the contribution of global excitatory and inhibitory neuronal activity to RTT phenotypes. Ultimately, the proposal will provide important insight into MeCP2 regulation of neuronal function and the neurobiological alterations resulting in RTT pathogenesis and provide new target pathways for investigating potential therapeutic interventions. [unreadable] [unreadable]

PROJECT SUMMARY Technological advances have accelerated the discovery of genetic etiologies for many neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, and epilepsy. The emerging theme of altered inhibitory ?-aminobutyric-acid-(GABA)-ergic signaling in many of these disorders suggest a common pathogenic mechanism despite heterogeneous etiologies. Although comprising only ~20% of neurons in the brain, GABAergic neurons are key for virtually all aspects of neurobiology, from neural development to network dynamics, but there remains a knowledge gap regarding how genetic alterations perturb GABAergic signaling and result in cognitive and behavioral changes. This gap needs to be addressed in order to bridge molecular functions to disease mechanisms and expand our understanding of inhibitory neurobiology. We, and others, recently found that heterozygous loss-of-function (LOF) gene variants affecting evolutionarily conserved residues in EBF3 (Early B-cell Factor 3), a COE transcription factor, cause a neurodevelopmental disorder called Hypotonia Ataxia and Delayed Development Syndrome (HADDS, MIM#617330). EBF3 and the other mammalian COE factors are crucial for the development of inhibitory GABAergic neurons, but were not previously associated with neurologic disorders. These findings suggest that COE transcription factors are a novel group of genes in the pathogenesis of neurodevelopmental disorders. The overall goal of this project is to decipher the transcriptional dysregulation of inhibitory signaling in fly and mouse models of COE factor-related disorders and understand the relevance of these alterations to disease. Known molecular and cellular functions of COE factors in inhibitory GABAergic neuronal development leads to the hypothesis that altered COE transcription factor function perturb inhibitory signaling resulting in neurological deficits. I will combine human genomics and genetic manipulations in fly and mouse models with molecular, neurophysiological, and behavioral analyses to determine the role of COE factor dysfunction in neurodevelopmental disorders (Aim 1), delineate disrupted inhibitory signaling in EBF3-related disorders (Aim 2), and elucidate the mechanisms of COE transcription factor regulation of GABAergic signaling (Aim 3). This project shifts the research focus of COE transcription factors, and EBF3 in particular, from the molecular and cellular levels to neural networks and behaviors. These studies have the potential to provide mechanistic insights into the highly prevalent group of disorders distinguished by intellectual disability and autism. Furthermore, the gain in understanding of how transcriptional dysregulation of inhibitory neurons affects neural activity and behaviors will impact the growing list of disorders associated with abnormal inhibitory signaling.