# Electrical Stimulation of Immediate Early Genes

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $641,163

## Abstract

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.

## Key facts

- **NIH application ID:** 10138030
- **Project number:** 5R01NS028829-32
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** MICHAEL ELDON GREENBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $641,163
- **Award type:** 5
- **Project period:** 1990-08-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138030

## Citation

> US National Institutes of Health, RePORTER application 10138030, Electrical Stimulation of Immediate Early Genes (5R01NS028829-32). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10138030. Licensed CC0.

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