acase@tulane.edu / Major Depressive Disorder is a pervasive and devastating neuropsychiatric disease. One in three patients receive no therapeutic benefit from standard antidepressant treatments, and those who do respond do so only after chronic treatment for weeks to months. A single low dose of ketamine, an NMDA receptor antagonist, results in a rapid and prolonged antidepressant effect in as many as 90 percent of treatment-resistant patients. In this thesis we elucidate some mechanisms through which ketamine functions.
Here we demonstrate in mice that ketamine treatment initiates mTOR-dependent protein synthesis, increases expression of synaptic proteins, increases excitatory synaptic drive in mPFC, and elicits an antidepressant-like response. Furthermore, genetic deletion of NMDAR subunit GluN2B from cortical pyramidal neurons is sufficient to mimic and occlude ketamine’s effects on protein synthesis, excitatory synaptic function, and depression-related behaviors. We demonstrate that GluN2B-containing NMDARs are uniquely tonically activated by ambient glutamate in mPFC, and that altering levels of ambient glutamate bidirectional alters excitatory synaptic drive in mPFC and depression-related behaviors.
Next we demonstrate that viral deletion of GluN2B from pyramidal neurons in mPFC enhances excitatory synaptic drive onto these cells in an input-specific manner and is sufficient to elicit an antidepressant-like response.
Finally, using genome-wide profiling of translating mRNAs, we observe that antidepressant-dose ketamine enhances the expression of gene-sets involved in translational processes, metabolism, GPCR signaling, and angiogenesis, among others. Individual genes were analyzed for a potential role in ketamine’s antidepressant-like response, and we identified one GPCR, VPAC2, as being a candidate target.
This thesis contributes important steps towards a mechanistic understanding of ketamine’s effects as an antidepressant, and reveals novel targets for depression therapy. / 1 / Oliver H Miller
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_74433 |
| Date | January 2016 |
| Contributors | Miller, Oliver (author), Hall, Benjamin (Thesis advisor), School of Science & Engineering Neuroscience (Degree granting institution) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Detected Language | English |
| Format | electronic, 168 |
| Rights | 12 months, Copyright is in accordance with U.S. Copyright law. |
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