Friday, May 9, 2025
5/9/2025
Genomic Mechanisms of BDNF Signaling in the Brain - PROJECT SUMMARY/ABSTRACT Sensory experience shapes the maturation of neural circuits during critical periods of development. How early- life experience modifies synaptic connectivity to refine sensory information processing remains a central question in neurobiology. Neurons respond to external sensory experience through the rapid, activity-dependent transcription of immediate early gene (IEG) transcription factors (TFs), such as Fos, Npas4, and Egr1. Once expressed, IEGs regulate a wave of late-response genes (LRGs) that mediate the influence of activity on synaptic remodeling in a cell type-specific manner. In particular, activity-dependent transcription of the neurotrophin Bdnf/BDNF within excitatory neurons establishes the critical period for ocular dominance plasticity in the visual cortex by promoting the formation of inhibitory synapses onto excitatory neuron cell bodies. However, specific mechanisms by which BDNF mediates this unique form of synaptic plasticity, known as somatic inhibition, remain poorly understood. Although BDNF influences gene transcription, whether BDNF regulates transcription within specific neuron types to direct inhibitory synapses onto neuronal soma is not yet known. This project seeks to identify and characterize the genomic mechanisms by which BDNF regulates somatic inhibition in the mouse visual cortex. Aim 1 of this proposal uses a transgenic mouse line that lacks activity-dependent Bdnf transcription to identify BDNF-regulated genes and gene regulatory elements during visual cortex development. The experiments in Aim 1 test the hypothesis that BDNF regulates the transcription of key synaptic organizer genes in a cell type-specific manner to drive the formation of somatic inhibitory synapses. Aim 2 of this proposal seeks to identify specific IEG TFs that mediate the effects of BDNF on transcriptional activation. Recently, I discovered that the neuron-specific IEG TF, Egr4/EGR4, preferentially responds to BDNF in primary cortical neurons and binds the NuA4/TIP60 histone acetyltransferase complex in vitro. In this aim, I will use immunoprecipitation mass spectrometry and CUT&RUN to determine the interaction partners and genomic binding sites of EGR4 in mouse visual cortex. Given that NuA4/TIP60 both activates transcription and repairs transcription-coupled DNA double- strand breaks (DSBs), I will further test the hypothesis that EGR4 mediates BDNF-dependent DSB repair. Collectively, the proposed studies will provide novel insights into how BDNF regulates the maturation of cortical circuits and, more broadly, how neurons achieve stimulus-specific transcriptional regulation and genomic maintenance. Improved understanding of these processes will inform the study of neurological disorders that display a loss of BDNF production, including Alzheimer’s and Huntingtin’s disease.
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