Our goal is to identify activity-driven cellular and molecular mechanisms underlying synaptic plasticity and circuit refinement during development of central visual pathways. Understanding these mechanisms is crucial to facilitating recovery of functional vision following early visual disruption due to cataract, strabismus or trauma. Such understanding is also crucial to developing visual prosthetics, because these devises must effectively reactivate synaptic plasticity in latent brain circuitry. Our proposed studies use manual control of eye opening (EO) in rodents to synchronize synaptic maturation and plasticity in the superficial visual layers of the superior colliculus (sSC) and in the visual cortex (VC) neurons projecting to the sSC, the corticotectal projection (CTP). Synaptic changes caused specifically by EO (rather than age) can be identified by using, as controls, age-matched littermates whose eyes are prevented from opening. With this procedure we have documented a short period of rapid synaptic change after EO due, we postulate, to pattern vision driving the central visual pathway for the first time. Here we propose to study the effect of controlled EO on the VC layer 5 neurons that mature their axon terminals in the sSC during this eye-opening interval, determine if VC input is necessary for EO-associated changes found in the sSC, and identify molecular mechanisms underlying this change.
In Specific Aim I, we will determine whether perturbation of VC activity by ablation, blockade of NR glutamate receptors, and inhibitory RNA (RNAi) reductions of the major post-synaptic density scaffolding molecule PSD-95 before EO disrupt changes in sSC or VC that normally we find tightly associated with EO.
In Specific Aim II, we will test the hypothesis that the activity-dependent release of neurotrophin BDNF at visual synapses is responsible for initiating the rapid trafficking of the PSD-95 scaffold to excitatory synapses on central visual neurons, which occurs upon EO and may be responsible for many subsequent changes. These studies will use an in vitro assay of BDNF induced trafficking in VC and sSC neurons and a conditional BDNF KO mouse to test the BDNF hypothesis in vivo.
In Specific Aim III, we will continue a productive collaboration with the H.R. Horvitz laboratory in our department to study the expression of microRNAs (small -22 bp RNAs that control protein expression mostly by blocking protein translation). Using the controlled EO paradigm we will determine if changes in miRNA regulation are caused by the EO event. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY006039-25
Application #
7214676
Study Section
Central Visual Processing Study Section (CVP)
Program Officer
Steinmetz, Michael A
Project Start
1983-04-01
Project End
2011-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
25
Fiscal Year
2007
Total Cost
$388,793
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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