Investigation of Structural Plasticity Mechanisms in the Mammalian Visual System

Visually-driven experience early in postnatal life modulates the development of neuron structure and the arrangement of neural connections in the visual system. A disruption to visual experience during this formative period, as can occur with congenital cataracts or misaligned eyes, causes the structure of neurons within visual brain areas to develop abnormally and can result in severe visual impairments. The objective of this research is to provide a fundamental understanding of the cellular events that enable the modification of neuron structure (plasticity) in the context of circumstances that lead to functional impairments. Through this work we aim to facilitate the development of novel strategies to enhance neural plasticity in the pursuit of more effective ways to promote neural recovery. Inherent in this objective is an attempt to understand the neural processes that naturally and progressively diminish the capacity for plasticity with age, and that consequently explain the limited neural recovery reported in juvenile and adult visual system. We will build upon our previous research showing that neural plasticity is reduced with age by the progressive accumulation of a collection of intracellular proteins called intermediate filaments. Once produced by neurons, these proteins are known to be highly susceptible to modification by phosphorylation, which we propose reduces plasticity by enhancing protein stability. We will measure the level of protein phosphorylation across development and during episodes of structural plasticity to determine if phosphorylation contributes as a plasticity ‘brake’, and furthermore whether its reduction is linked to neural recovery. In a related study we will measure the activity of several brain enzymes (proteases) with conceivable links to plasticity in order to determine if the modification of neurons is mediated by an active proteolytic removal of protein ‘brakes’ that constrain plasticity. In the final set of experiments we will investigate a novel hypothesis that the mechanisms of plasticity observed early in postnatal life are also present in the adult brain, but maintain a higher threshold for their engagement. We will examine this question by measuring the mechanistic similarity between plasticity induced at young and adult stages of development. These studies will offer new and important insight into the cellular events that naturally regulate neural plasticity with age, and that enable the structural modification of neurons during periods of abnormal visual input that are known to precipitate the development of functional impairments. Finally, we expect these studies will provide a clearer mechanistic understanding of the factors that yield poor neural plasticity outcomes initiated in adolescence and adulthood.