Leveraging synaptogenesis to understand and rapidly treat depression

Depression is one of humanity’s greatest health burdens. Major depressive disorder has a lifetime incidence of over 15% and is a leading cause of disability in the world. Standard antidepressants take weeks to develop their effects and for many patients, no classical treatments succeed. Studies beginning in 1980s have documented that a single dose of anesthetic ketamine leads to rapid, lasting relief from depression. How ketamine and newer analogous drugs work is unknown, either at the level of individual neuronal connections or activity patterns in groups of neurons. We will use cutting-edge multiphoton techniques, molecular genetic approaches and electrophysiology to precisely characterize structural and functional changes that occur on genetically-defined neurons in response to several fast-acting antidepressants, including Glyx-13, a promising candidate developed at Northwestern University Chemistry Department. Next we will determine how these mechanistic effects translate into the neural signature, or activity pattern, required for rapid antidepressant effects. Our work will forge the path towards a deeper understanding of currently available and under development rapid antidepressants, as well as identify directions for future drug targets and non-invasive therapies.