# Neuregulin-1 based molecular mechanisms of cortical plasticity

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $422,868

## Abstract

The physiological aspects of experience-dependent critical period plasticity has been extensively studied
starting with the pioneering studies of Hubel and Wiesel in the 1960s. However the molecular mechanisms that
translate sensory deprivation into functional changes in circuit connections remain poorly understood.
Neuregulin-1 (NRG1) signaling through its tyrosine kinase receptor ErbB4 is essential for the normal
development of the nervous system, and has been linked to neuropsychiatric disorders such as schizophrenia.
NRG1 is widely expressed in excitatory neurons, inhibitory interneurons and glial cells in the visual cortex, while
ErbB4 expression is largely restricted to parvalbumin-expressing (PV) neurons. We discovered recently that
NRG1/ErbB4 signaling in PV neurons is critical for the initiation of critical period visual cortical plasticity by
controlling excitatory synaptic inputs onto PV neurons and thus PV-cell mediated cortical inhibition that occurs
following visual deprivation. Building on the strong premise from the literature, this discovery and our data
showing that NRG1 effects depend on specific neuronal types and are modulated further by deprivation duration,
we propose to provide a detailed analysis of NRG1 signaling actions implicated in visual cortical plasticity at the
cellular and circuit levels. We hypothesize that NRG1 signaling critically regulates functional circuit connections
of PV inhibitory interneurons during short and prolonged visual deprivation that underlies the initiation and
establishment of visual critical period cortical plasticity. We also hypothesize that manipulation of ErbB4
signaling in PV neurons is sufficient to extend the ocular dominance plasticity after the closure of the critical
period. To test our hypotheses, in Aim1, we will use our established cell-type specific mRNA expression analysis
and neurochemical immunostaining to map cellular NRG1 expression in normal and deprived cortex, and
determine whether non-PV cell types contribute to the source of PV neuron NRG1. In Aim 2, we will combine
ex vivo functional circuit mapping and in vivo 2-photon calcium imaging to test whether NRG1/ErbB4 signaling
is required for maintenance of PV neuron excitatory inputs in normal cortex and for restoration of their excitatory
inputs in deprived cortex. In Aim 3, we will use pharmacological and genetic approaches to manipulate ErbB4
signaling in PV neurons to extend and attempt to re-open the critical period window of cortical plasticity. Together
the proposed research will advance our understanding of molecular mechanisms underlying visual cortical
plasticity, and help to develop new therapeutic approaches to treat amblyopia and other neurodevelopmental
disorders.

## Key facts

- **NIH application ID:** 9934205
- **Project number:** 5R01EY028212-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Sunil Gandhi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,868
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934205

## Citation

> US National Institutes of Health, RePORTER application 9934205, Neuregulin-1 based molecular mechanisms of cortical plasticity (5R01EY028212-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934205. Licensed CC0.

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