Friday, April 4, 2025
4/4/2025
Functional Mapping of Chd1-dependent Signaling Network in Synaptic Homeostasis - Abstract Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by significant developmental, intellectual, and behavioral impairments. Patients with ASD exhibit comorbid conditions and common features shared with epilepsy and intellectual disability (ID), suggesting an overlapping underlying etiology for these disorders. Human genetic studies have been extremely fruitful in identifying risk genes implicated in ASD and other neurodevelopmental disorders. One large group of such genes encodes chromatin remodeling proteins, while another encompasses synaptic molecules. Although it is known that chromatin remodelers are important for neuronal cell differentiation and development, the manner in which their abnormal activities affect synaptic function remains unclear. Synapses are highly dynamic, yet their electrical properties are stabilized within a physiological range throughout life by mechanisms of synaptic homeostatic plasticity. Dysregulation of synaptic homeostatic plasticity can lead to an imbalance of excitation and inhibition within neural networks, which is associated with chronic neurological disorders. Understanding how chromatin remodeling proteins and synaptic proteins functionally converge to control synaptic homeostatic plasticity - and how dysregulation of these proteins contributes to increased ASD susceptibility at molecular and cellular levels - is crucial. De novo Single Nucleotide Variants (SNVs) in the human Chromodomain Helicase DNA-binding Protein 2 (CHD2) have been associated with ASD, epilepsy, ID, and Attention-Deficit Hyperactivity Disorder (ADHD). We have discovered that Chd1, the Drosophila homolog of mammalian CHD2, is essential for presynaptic homeostatic plasticity. Interestingly, Chd1 expressed in different cell types exhibits distinct roles in the rapid induction and long-term maintenance of presynaptic homeostatic plasticity. Through an electrophysiology-based genetic screen, we have identified multiple downstream target genes of Chd1 that are critical for presynaptic homeostatic plasticity. This proposal seeks to investigate how Chd1-controlled downstream signaling pathways are functionally integrated both temporally and spatially within synaptic homeostatic plasticity. Furthermore, we aim to elucidate the mechanisms by which human disease variants in CHD2 impact synaptic physiology and homeostatic plasticity. Employing a multifaceted approach that includes genetic tools, electrophysiological methods, super-resolution imaging, transcriptomics, and computational analyses, we will systematically delineate the signaling domains regulated by Chd1 and generate a comprehensive understanding of the Chd1- dependent signaling network that stabilizes synaptic function.
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