Synaptic plasticity basis of fast antidepressant action

Major depressive disorder is a leading cause of disability in the world. Standard antidepressants take weeks to develop their effects and often the first prescribed medications are inadequate, extending the period of human suffering. In many patients, no standard treatments succeed. Studies beginning in 1980s have documented that a singe, sub-anesthetic dose of narcotic ketamine leads to rapid improvement of symptoms of major depression. Ketamine acts on the brain’s primary excitatory neurotransmitter systems, but its effects are incompletely understood. Also, which groups of neurons underlie the apparent clinical effect of ketamine is unknown. Two major goals of this proposal are to describe how ketamine alters the structure and function of excitatory connections between neurons and to determine the classes of neurons most sensitive to its effects. In addition, the fast antidepressant actions of ketamine have inspired the development of other drugs acting on the same systems. So, another goal of this project is to study a second promising drug currently in clinical studies and to compare its effects to those of ketamine. Our new laboratory is ideally poised to carry out these studies using cutting edge genetic and multi-photon imaging tools. In time, we hope to advance the development of new compounds impinging upon identified plasticity mechanisms and to improve the targeting of human therapies.