The proper functioning of the mature visual system depends upon experience-dependent refinement of cortical circuitry during early postnatal development. Visual deprivation during this early "critical period" (CP) can lead to loss of visual responsiveness to the deprived eye (amblyopia). Despite decades of research it is still unclear which cellular plasticity mechanism(s) contribute to this loss of visual responsiveness, and by extension are required for the normal development of visual function. For example, long-term depression (LTD) of cortical excitatory synapses has been suggested to be necessary and sufficient for loss of visual responsiveness following MD, while other studies have raised the possibility that potentiation of inhibition plays a critical role in this process. Recently the maturation of inhibition from fast-spiking GABAergic basket cells (FS cells) has been implicated in the regulation of CP onset, but why mature inhibition is necessary for CP plasticity is still unknown. During the past 2 funding periods we found that monocular deprivation (MD) during the rodent CP dramatically potentiates inhibitory transmission at FS synapses onto star pyramidal neurons (SP, the major excitatory cell type within L4 of rodent V1), by inducing a novel form of long-term potentiation of inhibition (LTPi) at this synapse. Further, LTPi is developmentally regulated, turns on coincidently with the opening of the CP, and manipulations that delay or advance the CP also delay or advance the ability of FS synapses to express LTPi. In this proposal we wish to test the central hypothesis that LTPi plays a critical role in the lossof visual responsiveness induced by visual deprivation, so that FS cells initiate the CP by gaining the ability to express LTPi. To this end we will exploit our mechanistic understanding of LTPi to block its induction in vivo, and determine the role LTPi plays in the cortical response to monocular deprivation (MD). Further, we will evaluate the relative importance of LTD and LTPi in MD-induced loss of visual responsiveness within L4, and ask whether these two forms of plasticity are induced in a synergistic manner during MD. We will combine in vivo and in vitro electrophysiology, viral-mediated gene transfer, and optogenetics to achieve these goals. These experiments will settle a long-standing debate about the mechanisms underlying amblyopia, and have the potential to radically alter our view of the cellular underpinnings of CP plasticity. )

Public Health Relevance

Amblyopia, or reduced vision due to the effects of early abnormal visual experience, affects approximately 3% of the human population. Designing effective treatments requires an understanding of the cellular and molecular mechanisms that underlie this process, but despite decades of work the synaptic plasticity mechanisms that underlie vision loss due to visual deprivation during developmental sensitive periods are still intensely debated. The experiments in this proposal will definitively establish the relative roles f these two forms of plasticity, and have the potential to suggest new avenues of treatment for amblyopia.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY014439-09
Application #
8370714
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Steinmetz, Michael A
Project Start
2002-12-01
Project End
2016-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$402,500
Indirect Cost
$152,500
Name
Brandeis University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454
Nahmani, Marc; Turrigiano, Gina G (2014) Deprivation-induced strengthening of presynaptic and postsynaptic inhibitory transmission in layer 4 of visual cortex during the critical period. J Neurosci 34:2571-82
Nahmani, M; Turrigiano, G G (2014) Adult cortical plasticity following injury: Recapitulation of critical period mechanisms? Neuroscience 283:4-16
Hengen, Keith B; Lambo, Mary E; Van Hooser, Stephen D et al. (2013) Firing rate homeostasis in visual cortex of freely behaving rodents. Neuron 80:335-42
Nataraj, Kiran; Turrigiano, Gina (2011) Regional and temporal specificity of intrinsic plasticity mechanisms in rodent primary visual cortex. J Neurosci 31:17932-40
Nataraj, Kiran; Le Roux, Nicolas; Nahmani, Marc et al. (2010) Visual deprivation suppresses L5 pyramidal neuron excitability by preventing the induction of intrinsic plasticity. Neuron 68:750-62
Maffei, Arianna; Lambo, Mary E; Turrigiano, Gina G (2010) Critical period for inhibitory plasticity in rodent binocular V1. J Neurosci 30:3304-9
Bracken, Bethany K; Turrigiano, Gina G (2009) Experience-dependent regulation of TrkB isoforms in rodent visual cortex. Dev Neurobiol 69:267-78
Turrigiano, Gina G (2008) The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135:422-35
Maffei, Arianna; Turrigiano, Gina G (2008) Multiple modes of network homeostasis in visual cortical layer 2/3. J Neurosci 28:4377-84
Sjostrom, Per Jesper; Turrigiano, Gina G; Nelson, Sacha B (2007) Multiple forms of long-term plasticity at unitary neocortical layer 5 synapses. Neuropharmacology 52:176-84

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