Exploiting principles of timing-dependent synaptic plasticity to treat amblyopia

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This proposal describes a 5-year training program for the development of an academic career focused on improving therapy for amblyopia by advancing our understanding and exploitation of synaptic plasticity mechanisms. My graduate training in electrophysiology and synaptic plasticity carried through during my ophthalmology residency and neuro-ophthalmology fellowship at Massachusetts Eye and Ear Infirmary (MEEI) and Harvard Medical School (HMS). During this time, I have been working in the laboratory of Dr. Mark Bear at the nearby Massachusetts Institute of Technology (MIT) gathering early data on a potential new therapeutic approach for amblyopia. This work will continue during my pediatric ophthalmology fellowship at Boston Children’s Hospital (BCH) through July 2019. I wish to continue this research and my development to prepare for an independent research career. My long-term goals include making major contributions to the understanding of the synaptic mechanisms underlying amblyopia while providing translational insights that can yield new therapeutic approaches for patients with central visual dysfunction. Dr. Bear, a world expert on amblyopia and synaptic physiology and plasticity with a proven track record of productivity and mentorship, will serve as mentor. An advisory committee comprised of Drs. David Hunter (BCH/HMS), Ed Boyden (MIT), and Peter Bex (Northeastern University) will guide my research and career development. This MEEI-sponsored project will take place in the rich environments of MIT, with access to resources at MEEI, BCH and HMS. The proposed research program examines interocular temporal phase offset training (TPOT), which is predicated on timing-dependent principles of synaptic plasticity, as a potential new therapeutic approach to amblyopia while elucidating properties of signal integration in visual cortex. In our initial experiments, we show that TPOT is sufficient to selectively strengthen visually evoked potentials in the inherently weaker ipsilateral eye and shift ocular dominance in mice. In the first Aim, I will characterize the properties of TPOT, including stimulus selectivity, optimal parameters for efficacy and age limits. I will define the interaction of signal phase with contrast reduction, which has been used to treat amblyopia, and determine the cortical laminar-specific effects of TPOT. The second Aim is to gain mechanistic insights into the TPOT effect. I will learn and apply 2- photon calcium imaging techniques to define the ocular dominance shift at the neuronal level, and selectively target NMDA receptor expression in the visual cortex to uncover their role in TPOT-induced visual cortical plasticity. The third Aim will apply TPOT to monocularly deprived mice, a widely studied animal model for amblyopia, with the goals of promoting visual recovery and generalizing the TPOT effect. In conducting these experiments, I will gain considerable experience with advanced techniques to study murine visual physiology in the context of amblyopia, thereby providing me with crucial technical, conceptual and professional foundations to build my early career as an independent clinician-scientist and future contributor and expert to the field.