Sensory experience powerfully regulates late postnatal development and adult function of brain circuits, particularly in the cerebral cortex. The cellular mechanisms that mediate this process are not yet understood, but have major implications for understanding cortical neurodevelopmental disorders, including autism, juvenile epilepsy, and mental retardation. This project focuses on novel mechanisms by which experience controls the balance of excitation and inhibition in cerebral cortex. This is studied in the somatosensory cortex of rodents, which is a canonical model system for cortical function. Standard models of experience-dependent development and modification (plasticity) focus on excitatory cortical circuits. However, recent findings indicate that inhibitory circuits also show robust plasticity by sensory experience. The prevalence, cellular mechanisms, and mechanistic role of inhibitory plasticity are largely unknown. Using cellular and systems-level neurophysiology techniques, we will identify specific inhibitory neurons and circuits that are regulated by sensory experience, characterize the cellular mechanisms for this plasticity, and determine its role in cortical function. We specifically test the hypothesis that inhibitory plasticity has a dual role: to maintain excitatory-inhibitory balance, and to mediate rapid homeostasis of sensory responses during changing sensory use. Substantial preliminary data support the proposal. Overall, this work will extend our understanding of cortical development beyond basic plasticity of excitatory circuits, to include rapid, robust plasticity of inhibition. Results may suggest a novel basis for neurodevelopmental disorders including juvenile epilepsy and autism, which may arise from improper development of excitatory-inhibitory balance. This work may lead to improved animal models and novel therapeutic strategies for these diseases.

Public Health Relevance

This research will identify the cellular mechanisms for an important postnatal phase of brain development in which sensory experience refines and optimizes circuits in the brain's cerebral cortex. The project focuses on novel mechanisms that control the balance of excitation and inhibition in the brain. This basic knowledge of brain development is critical for improving our understanding of neurodevelopmental disorders of the cerebral cortex, including autism, juvenile epilepsy, and mental retardation, and may lead to improved animal models and therapeutic strategies for these diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Gnadt, James W
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University of California Berkeley
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United States
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Gainey, Melanie A; Aman, Joseph W; Feldman, Daniel E (2018) Rapid Disinhibition by Adjustment of PV Intrinsic Excitability during Whisker Map Plasticity in Mouse S1. J Neurosci 38:4749-4761
Gainey, Melanie A; Feldman, Daniel E (2017) Multiple shared mechanisms for homeostatic plasticity in rodent somatosensory and visual cortex. Philos Trans R Soc Lond B Biol Sci 372:
Keck, Tara; Toyoizumi, Taro; Chen, Lu et al. (2017) Integrating Hebbian and homeostatic plasticity: the current state of the field and future research directions. Philos Trans R Soc Lond B Biol Sci 372:
Gainey, Melanie A; Wolfe, Renna; Pourzia, Olivia et al. (2016) Whisker Deprivation Drives Two Phases of Inhibitory Synapse Weakening in Layer 4 of Rat Somatosensory Cortex. PLoS One 11:e0148227
Li, Lu; Gainey, Melanie A; Goldbeck, Joseph E et al. (2014) Rapid homeostasis by disinhibition during whisker map plasticity. Proc Natl Acad Sci U S A 111:1616-21
Shao, Yu R; Isett, Brian R; Miyashita, Toshio et al. (2013) Plasticity of recurrent l2/3 inhibition and gamma oscillations by whisker experience. Neuron 80:210-22
Feldman, Daniel E (2012) The spike-timing dependence of plasticity. Neuron 75:556-71
House, David R C; Elstrott, Justin; Koh, Eileen et al. (2011) Parallel regulation of feedforward inhibition and excitation during whisker map plasticity. Neuron 72:819-31