Administrative Supplement: Reversible activation of critical period plasticity in visual cortex

Univ Of Maryland, College Park, College Park MD

Investigators

Linked publications & trials

Abstract

Summary/Abstract of parent award 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. 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 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 Pyr->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 Pyr->PV-IN plasticity, which departs from many widely-held assumptions regarding developmental changes in synaptic plasticity in the mammalian cortex. Supplemental activities to expand the that proposed in the parent award (expanded in research design) Models of enhanced plasticity via disinhibition of pyramidal neurons, including the one tested in the parent award, assume that the increase in neuronal activity promotes plasticity through correlative spiking. However, there is very little evidence to support this prediction in any model system, especially in vivo. Here a new graduate student in the Quinlan lab, Laura Ixchel Castillo, proposes to measure neuronal activity throughout the primary visual cortex in awake head-fixed mice through chronically-implanted micro electrodes arrays. She will measure changes in network activity, spike correlation and spike-phase synchrony at multiple time points before and after monocular deprivation during the mouse critical period. We predict that following 1 day of monocular deprivation, the time point at which we observed the disconnection of local excitatory drive to PV Interneurons, there will be an increase in pairwise correlation between proximal neurons and an increase in spike-phase coupling. This will be transient, and return to normal control values by 3 days of MD. These predictions are consistent with, and extend, the work of the parent award.