Significant progress has been made recently towards understanding the molecular mechanisms that control synapse development in the mammalian brain. Our laboratory has uncovered a role for the activity-regulated bHLH transcription factor, Npas4, in the development of inhibitory synapses onto excitatory neurons and resulting effects on the balance between inhibitory and excitatory synapses. To understand the mechanism by which Npas4 controls inhibitory synapse development in vivo, we have generated mice that carry a cre-mediated conditional knockout mutation of f lpas4 Using this conditional knockout approach, we will examine the effect of loss of Npas4 on inhibitory synapse formation and function at various times during development. We will also use this mouse model to test the role of Npais4 on inhibitory synapse maturation and sensory experience-mediated synaptic plasticity in the developing visual cortex. In addition, we will use a combination of chromatin immunoprecipitation-sequencing and transcriptome-sequencing in conjunction with bioinformatics analysis to identify on a genome-wide scale the DNA occupancy sites of Npas4 and the RNA transcripts that Npas4 regulates. These studies will provide new insights into the genetic program that Npas4 controls to mediate its effect on inhibitory synapse development and the balance between excitatory and inhibitory inputs in the mammalian brain. These studies will be crucial to our understanding of how disorders of cognitive function such as autism spectrum disorders may arise when the delicate excitatory/inhibitory balance is disrupted and may suggest targets for treatments of these diseases.

Public Health Relevance

As defects in the balance between excitation and inhibition can lead to disorders of cognitive function such as autism spectrum disorders, understanding how this delicate balance is established and maintained is crucial for the discovery of therapies to treat or prevent these diseases of cognition.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Mardinly, A R; Spiegel, I; Patrizi, A et al. (2016) Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons. Nature 531:371-5
Lou, Shan; Pan, Xiaoxin; Huang, Tianwen et al. (2015) Incoherent feed-forward regulatory loops control segregation of C-mechanoreceptors, nociceptors, and pruriceptors. J Neurosci 35:5317-29
Labidi-Galy, S I; Clauss, A; Ng, V et al. (2015) Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors. Oncogene 34:373-83
Doherty, Michael F; Adelmant, Guillaume; Cecchetelli, Alyssa D et al. (2014) Proteomic analysis reveals CACN-1 is a component of the spliceosome in Caenorhabditis elegans. G3 (Bethesda) 4:1555-64
Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616-20
Ficarro, Scott B; Biagi, Jessica M; Wang, Jinhua et al. (2014) Protected amine labels: a versatile molecular scaffold for multiplexed nominal mass and sub-Da isotopologue quantitative proteomic reagents. J Am Soc Mass Spectrom 25:636-50
Bergthold, Guillaume; Bandopadhayay, Pratiti; Bi, Wenya Linda et al. (2014) Pediatric low-grade gliomas: how modern biology reshapes the clinical field. Biochim Biophys Acta 1845:294-307
Lim, Sang Min; Westover, Kenneth D; Ficarro, Scott B et al. (2014) Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor. Angew Chem Int Ed Engl 53:199-204
Lu, Yu; Loh, Yuin-Han; Li, Hu et al. (2014) Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells. Cell Stem Cell 15:92-101
Silbereis, John C; Nobuta, Hiroko; Tsai, Hui-Hsin et al. (2014) Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain. Neuron 81:574-87

Showing the most recent 10 out of 50 publications