Neurobiology of Stress, Depression, and Antidepressants: Remodeling Synaptic Connections

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Chronic stress and depression decrease neurotrophic factor expression, dendrite complexity, and synaptic density, contributing to reduced volume of prefrontal cortex (PFC) and hippocampus in depressed patients. Conversely, blocking or reversing the neurotrophic and synaptic deficits caused by stress produces antidepressant responses in rodents. Typical monoaminergic antidepressants have limited efficacy to alter synaptic deficits associated with stress and depression, which could account for the time lag and low response rates of these agents. Recent studies demonstrate that the NMDA receptor antagonist ketamine produces rapid (within hours) antidepressant effects in treatment resistant depressed patients, addressing these limitations. Importantly, ketamine causes rapid, activity dependent release of BDNF, stimulation of mTORC1 signaling, and increased synthesis of synaptic proteins that rapidly reverse the atrophy of PFC neurons caused by chronic stress. Deficits in mTORC1 signaling, as well as BDNF, contribute to the synaptic deficits caused by chronic stress and depression, indicating that mTORC1 activation could be a novel approach for drug development. Despite this progress, the cellular mechanisms underlying the actions of ketamine remain unclear. In particular, whether ketamine acts directly on glutamate pyramidal neurons or indirectly via blockade of GABA neurons has not been determined. Using a viral mediated, cell specific shRNA approach we have found that knockdown of GluN2B on GABA interneurons but not glutamate neurons in the PFC blocks the antidepressant behavioral actions of ketamine. These findings indicate that ketamine blockade of tonic firing GABA interneurons results in a transient burst of glutamate that causes long-lasting changes in synapse number and function that underlie the rapid and sustained antidepressant actions of ketamine. Studies are being conducted to determine if other rapid acting antidepressants, including the ketamine metabolite, (2R, 6R)-hydroxynorketamine and the glycine-like partial agonist Repastinel, act via a similar cellular trigger mechanism and to determine which types of GABA interneurons, somatostatin or parvalbumin, mediate the actions of ketamine. Together these studies further characterize the pathophysiology of stress and depression and the mechanisms by which rapid antidepressants rescue this pathology, and could lead to new targets for the development of rapid and efficacious antidepressants without the side effects of ketamine.