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Reversible activation of critical period plasticity in visual cortex

视觉皮层关键期可塑性的可逆激活

基本信息

批准号：
10815219
负责人：
Alfredo Kirkwood
金额：
$ 8.18万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2025-07-31
项目状态：
未结题

项目摘要

Project Summary/Abstract Amblyopia is induced in model systems by monocular deprivation (MD), which changes the stimulus selectivity of neurons in the primary visual cortex. Prior research utilizing this model established that the changes in neural selectivity induced by MD result from the reorganization of excitatory glutamatergic cortical synapses onto excitatory cortical neurons, which is regulated by an inhibitory GABAergic network composed of parvalbumin positive inhibitory interneurons (PV INs). An emerging consensus is that a permissive level of inhibition from PV IN circuits in cortical layer 2/3 is required for plasticity at downstream excitatory synapses, and that inhibition above or below the permissive range constrains the response to MD. Accordingly, developmental strengthening of inhibition triggers the onset of the critical period; at later stages, the “permissive” range of inhibition is achieved by reductions the recruitment of PV INs. Here we identify the plasticity of excitation onto layer 2/3 PV INs as a critical locus for the regulation of circuit reorganization in V1. Our preliminary data demonstrate that the initial response to MD is a rapid and transient elimination of excitatory connections made by local pyramidal neurons (Pyr) onto PV INs. Following 1 day of MD, we find that ~50% of local L2/3 PyràPV-IN connections are eliminated. Importantly, synapses from distal L2/3 Pyrs and excitation from layer 4 Pyrs remains unchanged. This all-or-none elimination of specific connections coincides with the loss of synaptic structure, is transient, and returns to control values following 3 days of MD. Our preliminary results also demonstrate that the MD-induced elimination of proximal L2/3 PyràPV INs inputs depends on mGluR5 activation and is inhibited by expression of activity-independent neuronal pentraxin 2 (NPTX2). We propose that the rapid mGluR5 and NPTX2-dependent elimination of local L2/3 PyràPV INs connection is an obligatory initial step for subsequent changes in ocular dominance and spatial acuity induced by MD. Accordingly, we show that accumulation of NPTX2 prevents L2/3 PyràPV IN elimination and ocular dominance plasticity. Conversely, expression of dominant negative NPTX2 in adults reactivates the elimination of L2/3 PyràPV INs and ocular dominance plasticity in response to MD We propose a series of multidisciplinary experiments to test the validity of this model that combine the expertise of the Quinlan lab in the assessment of physiological changes in vivo physiology and the Kirkwood lab in the assessment of changes in single synapses between identified neurons. We will test the hypothesis that the elimination of L2/3 PyràPV INs excitatory synapses is 1) local, transient and confined to a postnatal critical period 2) dependent on mGluR and NPTX2 signaling and 3) an obligatory initial step for subsequent changes in ocular dominance and spatial acuity induced by MD. Our model predicts that the end of the critical period reflects directly the loss of L2/3 PyràPV-IN plasticity, which departs from many widely-held assumptions regarding developmental changes in synaptic plasticity in the mammalian cortex.

项目总结/文摘