title: Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period.
abstract: Maturation of excitatory drive onto fast-spiking interneurons (FS INs) in the visual cortex has been implicated in the control of the timing of the critical period for ocular dominance plasticity. However, the mechanisms that regulate the strength of these synapses over cortical development are not understood. Here we use a mouse model to show that neuregulin (NRG) and the receptor tyrosine kinase erbB4 regulate the timing of the critical period. NRG1 enhanced the strength of excitatory synapses onto FS INs, which inhibited ocular dominance plasticity during the critical period but rescued plasticity in transgenics with hypoexcitable FS INs. Blocking the effects of endogenous neuregulin via inhibition of erbBs rescued ocular dominance plasticity in postcritical period adults, allowing recovery from amblyopia induced by chronic monocular deprivation. Thus, the strength of excitation onto FS INs is a key determinant of critical period plasticity and is maintained at high levels by NRG-erbB4 signaling to constrain plasticity in adulthood.
  
  
  
  Despite decades of experimentation, the mechanisms by which critical periods of enhanced synaptic plasticity are initiated and terminated are not completely understood. Here we show that neuregulin (NRG) and the receptor tyrosine kinase erbB4 determine critical period timing by controlling the strength of excitatory synapses onto FS INs. NRG1 enhanced excitatory drive onto fast spiking interneurons, which inhibited ocular dominance plasticity in juveniles but rescued plasticity in transgenics with hypoexcitable FS INs. Blocking the effects of endogenous neuregulin via inhibition of erbBs rescued ocular dominance plasticity in adults, allowing recovery from amblyopia induced by chronic monocular deprivation. Thus, in contrast to prevailing views of the termination of the critical period, active maintenance of strong excitation onto FS INs constrains plasticity in adults.
authors.affiliation: Neuroscience and Cognitive Science Program, Department of Biology, University of Maryland, College Park, Maryland 20742, and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Mind/Brain Institute, Johns Hopkins University, Baltimore, Maryland 21218.
authors.forename: Trinh
authors.initials: T
authors.lastname: Tran
authors.affiliation: Neuroscience and Cognitive Science Program, Department of Biology, University of Maryland, College Park, Maryland 20742, and.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Murase
authors.affiliation: Neuroscience and Cognitive Science Program, Department of Biology, University of Maryland, College Park, Maryland 20742, and.
authors.forename: Andrew
authors.identifier: 0000-0002-2986-9573
authors.initials: A
authors.lastname: Borrell
authors.affiliation: Mind/Brain Institute, Johns Hopkins University, Baltimore, Maryland 21218 equinlan@umd.edu kirkwood@jhu.edu.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Kirkwood
authors.affiliation: Neuroscience and Cognitive Science Program, Department of Biology, University of Maryland, College Park, Maryland 20742, and equinlan@umd.edu kirkwood@jhu.edu.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Quinlan
mesh_terms: D000550:Amblyopia / Q000503:physiopathology; D000818:Animals; D003423:Critical Period, Psychological; D023882:Dominance, Ocular / Q000502:physiology; D005260:Female; D007395:Interneurons / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D066247:Receptor, ErbB-4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D020127:Recovery of Function / Q000235:genetics; D013569:Synapses / Q000502:physiology; D015349:Vision, Monocular / Q000502:physiology; D014793:Visual Cortex / Q000166:cytology / Q000502:physiology*
chemical_list: D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4
keywords: critical period; fast-spiking interneurons; neuregulin; ocular dominance plasticity; parvalbumin