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.

Public Health Relevance

The proposed research is to understand NRG1-directed molecular, cellular and circuit mechanisms that drive plasticity during the critical period. Our results will promote the development of novel therapeutic strategies to treat amblyopia and other critical period disorders. As NRG1 and ErbB4 have been genetically identified as schizophrenia 'at-risk' genes, the proposed research is also relevant to neural mechanisms of neuropsychiatric diseases including schizophrenia.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Greenwell, Thomas
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University of California Irvine
Anatomy/Cell Biology
Schools of Medicine
United States
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Grieco, Steven F; Holmes, Todd C; Xu, Xiangmin (2018) Neuregulin directed molecular mechanisms of visual cortical plasticity. J Comp Neurol :