Synaptic transmission leads to the activation of transcriptional programs in the postsynaptic cell that are critical for long-lasting changes in synaptic refinement and plasticity. While the finding that abnormalities in this signaling pathway are associated with human cognitive disorders underscores the importance of this activity-regulated network for proper circuit function, elucidation of the precise role played by this form of regulation in the dynamic modulation of specific synaptic connections within the context of a complex microcircuit has proven challenging. Our laboratory has sought to address these issues in the context of the murine hippocampus, uncovering a role for the activity-dependent transcription factor (TF) Npas4 in modulating inhibitory GABAergic inputs onto CA1 pyramidal cells. Building on these findings, we have recently characterized the differential regulation of perisomatic inputs from parvalbumin (PV)- and cholecystokinin (CCK)-positive interneurons in response to experience-driven neuronal activity, showing that this effect is dependent upon Npas4 action in the postsynaptic pyramidal cell and identifying Scg2 as a novel activity-regulated mediator of these forms of inhibitory synaptic plasticity. Taken together, these studies represent among the first insights into the mechanisms governing the activity-regulated control of perisomatic inhibition. Moreover, we have found Npas4 functions in a cell-type-specific manner to differentially modulate the connectivity of neuronal cell types via the induction of distinct neuronal cell-type-specific transcriptional programs. To gain insight into the basis of Npas4?s cell-type-specific functions and further advance our understanding of its role in the control of activity-induced inhibitory synaptic plasticity within the CA1 microcircuit, we propose (1) to investigate the mechanisms underlying cell-type-specific Npas4-mediated gene regulation, and (2) to characterize the role of Scg2 in activity-dependent perisomatic inhibitory plasticity. The proposed studies will advance our understanding of how this crucial microcircuit is modified by experience, allow for new insights into the mechanisms by which activity-regulated gene expression controls synaptic plasticity, and ultimately provide opportunities for the development of novel therapeutic interventions to address a range of neurodevelopmental and neuropsychiatric conditions.
Neuronal activity triggers the expression of new genes that play a critical role in aspects of neural development and cognitive function. The proposed study investigates how this regulatory mechanism contributes to experience-dependent neural plasticity in the central nervous system.
|Hrvatin, Sinisa; Hochbaum, Daniel R; Nagy, M Aurel et al. (2018) Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex. Nat Neurosci 21:120-129|
|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|
|Andzelm, Milena M; Cherry, Timothy J; Harmin, David A et al. (2015) MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers. Neuron 86:247-63|
|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|
|Chahrour, Maria H; Yu, Timothy W; Lim, Elaine T et al. (2012) Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet 8:e1002635|
|Hemberg, Martin; Gray, Jesse M; Cloonan, Nicole et al. (2012) Integrated genome analysis suggests that most conserved non-coding sequences are regulatory factor binding sites. Nucleic Acids Res 40:7858-69|
|Ross, Sarah E; McCord, Alejandra E; Jung, Cynthia et al. (2012) Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit assembly. Neuron 73:292-303|
|Ross, Sarah E; Mardinly, Alan R; McCord, Alejandra E et al. (2010) Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65:886-98|
|Kim, Tae-Kyung; Hemberg, Martin; Gray, Jesse M et al. (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465:182-7|
|Greer, Paul L; Hanayama, Rikinari; Bloodgood, Brenda L et al. (2010) The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140:704-16|
Showing the most recent 10 out of 41 publications