New Scholar Award in Aging
Skirball Institute - New York University School of Medicine
In Vivo Study of Age-related Changes in Synaptic Structure
Changes in synaptic structure are not just a developmental phenomenon but take place throughout the lifetime of the nervous system. While synaptic rearrangements are likely to play pivotal roles in long-term memory and functional recovery after nerve injury, loss of synapses in the elderly has been shown to correlate directly with decline in cognitive performance and may be involved in the pathogenesis of Alzheimer's disease. The aim of our study is to better understand how changes in synaptic structure occur in vivo and how they are regulated under normal and pathological aging conditions.
Our knowledge about synaptic alterations in vivo has been limited by the fact that dynamic events are inferred from single-time-point observations. Given the complexity and individual variability of synaptic connections in the nervous system, it is often difficult if not impossible, to reconstruct dynamic processes from static observations. To overcome this difficulty, we have pioneered a high-resolution in vivo confocal imaging technique to directly visualize the structural dynamics of individual synapses in Yellow Fluorescent Protein (YFP)-expressing transgenic mice. This in vivo imaging approach has allowed us to follow YFP-labeled synapses of individual neurons in the readily accessible mouse submandibular ganglion over an extended period of time (> 1 year), thus providing a direct window to study structural plasticity in the living animal.
By following synapses of the same neurons in vivo we will observe, for the first time, dynamic events that lead to changes in synaptic structure over periods ranging from minutes to months. We will examine how dynamic behavior of synapses changes with advancing age and how age-related synapse loss takes place. In addition, by over-expressing mutant amyloid precursor protein, a well-established Alzheimer's disease risk factor, we will determine whether amyloid deposition influences synaptic plasticity in vivo and whether synaptic loss occurs early in the pathogenesis of Alzheimer's disease.
Because neuronal activity is instrumental in the process leading to synaptic plasticity and potentiating cholinergic activity is one of the treatment strategies for Alzheimer's disease, we will observe changes in synaptic structure as the level of neuronal activity is modified. We will further determine the role of neuronal activity in preventing age-related synapse loss. It is hoped that these studies will lead to a better understanding of experience-dependent modification of synaptic structure in the mature nervous system and new therapeutic strategies for neurodegenerative diseases.