Synaptic transmission leads to the activation of a transcriptional program in the postsynaptic cell that is critical for long-lasting changes in synapse development and plasticity. A number of neurodevelopmental disorders have been linked to abnormalities in this activity-regulated transcriptional network, indicating that these signaling pathways are critical for cognitive development and function. For many years attention has been focused on identifying the proximal promoter regions of activity-regulated genes and on assessing activity- dependent gene function. During the previous funding period, we used genome-wide sequencing methods to discover thousands of neuronal activity-regulated distal enhancer elements that function in primary mouse cortical cultures, indicating that by focusing on proximal promoter elements we had failed to identify the vast majority of neuronal activity-responsive cis-regulatory elements. The discovery of activity-regulated enhancer is of significant interest because there is accumulating evidence implicating distal cis-regulatory elements in human disease. However, the basic mechanisms of stimulus-responsive enhancer function in neurons are not yet understood and we lack methods to rapidly and reversibly disrupt enhancer and promoter function so that the roles of these regulatory elements, and the genes they control, can be assessed. In the absence of such methods, it has been difficult to characterize the specific contributions of these gene regulatory mechanisms to neural development and plasticity. To begin to address these issues, we propose (1) to develop a generalizable approach to disrupt neuronal cis-regulatory element function, and (2) to use this new technology to test the importance of regulatory elements within the gene encoding Brain-derived neurotrophic factor (BDNF) for inhibitory circuit plasticity. Taken together, the proposed experiments will provide insight into regions of the genome that are not yet characterized but likely to have crucial functions during nervous system development and function. These studies will also lead to the development of new methods for the study of cis-regulatory elements, provide a better understanding of the mechanisms by which neural activity shapes the developing and mature nervous system, and yield new insights into the importance of activity-responsive cis- regulatory elements for human cognition and disease.
Neuronal activity triggers the expression of new genes, which play a critical role in aspects of neural development and human cognitive function. The proposed study will seek to develop new methods to explore the regulation and function of this gene expression program in the central nervous system.
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