Grant: CIHR Fellowship

Long-term memory formation requires synthesis of new proteins, which are the basic biological building blocks and function executors. Perplexingly, the tiny connections between brain cells, known as synapses, are often located far away from the cell body where proteins are thought to be made. Recent findings, however, show that hundreds of proteins are produced on-demand locally at synapses, but precisely how this local source relates to information storage in health and disease is unknown. I aim to reveal how this local protein synthesis determines memory formation specifically at some synapse types but not others. Synapse dysregulation is a hallmark of disorders such as Alzheimer's, amyotrophic lateral sclerosis, and Fragile X syndrome, which have increasingly been associated with abnormal activity in protein synthesis globally or even locally at synapses. For example, human clinical trials are already underway to treat Fragile X by targeting global protein synthesis, which would be the first-ever therapy of this disease. There is similarly the potential to treat Alzheimer's, Parkinson's, and epilepsy. However, non-discriminatory targeting of global protein synthesis can disrupt normal cellular processes and result in serious side effects. This has prompted me to examine how highly localized protein synthesis at synapses underlies information storage, which is key to facilitate rational drug design to treat major neurological disorders with high specificity and efficacy. Because synapses are micrometer sized and difficult to study, this area is presently a blank on the map. To answer what local translation does and how it acts at synapses, I will combine multidisciplinary strategies such as electrophysiological, molecular, and optical approaches. The study I propose here will greatly expand our understanding of how local protein synthesis determines learning and memory in health as well as disease.