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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Medicine
United States
Zip Code
Malik, Athar N; Vierbuchen, Thomas; Hemberg, Martin et al. (2014) Genome-wide identification and characterization of functional neuronal activity-dependent enhancers. Nat Neurosci 17:1330-9
Spiegel, Ivo; Mardinly, Alan R; Gabel, Harrison W et al. (2014) Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs. Cell 157:1216-29
Bloodgood, Brenda L; Sharma, Nikhil; Browne, Heidi Adlman et al. (2013) The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature 503:121-5
Kim, Tae-Kyung; Hemberg, Martin; Gray, Jesse M et al. (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465:182-7
Fiore, Roberto; Khudayberdiev, Sharof; Christensen, Mette et al. (2009) Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels. EMBO J 28:697-710
Flavell, Steven W; Kim, Tae-Kyung; Gray, Jesse M et al. (2008) Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60:1022-38
Flavell, Steven W; Cowan, Christopher W; Kim, Tae-Kyung et al. (2006) Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311:1008-12
Schratt, Gerhard M; Nigh, Elizabeth A; Chen, Wen G et al. (2004) BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci 24:7366-77
Chen, Wen G; Chang, Qiang; Lin, Yingxi et al. (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302:885-9
Chen, Wen G; West, Anne E; Tao, Xu et al. (2003) Upstream stimulatory factors are mediators of Ca2+-responsive transcription in neurons. J Neurosci 23:2572-81

Showing the most recent 10 out of 32 publications