A single, low dose of the n-methyl d-aspartate receptor (NMDAR) antagonist ketamine produces rapid anti-depressant actions in treatment-resistant depressed patients. This observation strongly supports a role for cortical NMDAR function in depression, which could lead to the generation of new disease models and novel therapeutic strategies. While it is clear that NMDAR antagonism causes a rapid increase in protein translation in cortical neurons, the exact mechanisms underlying these incredible effects remain unclear. One critical unanswered question is how does suppression of NMDAR signaling promote protein translation? NMDARs are heteromultimeric complexes containing two GluN1 subunits and two GluN2 subunits, the latter of which are encoded by four genes (GluN2A-D). Cortical NMDARs are dominated by GluN2A and GluN2B subunits. Recent data have shown that GluN2B-containing NMDARs can act to directly suppress mammalian/mechanistic target of rapamycin (mTOR)-mediated protein translation in cortical neurons, through a cellular signaling mechanism that is uniquely associated with this subunit. Based upon these data, an exciting hypothesis is that relief of GluN2B-mediated suppression of mTOR signaling is responsible for producing the rapid anti- depressant effects observed in response to low dose ketamine treatment. The experiments in this proposal will test this hypothesis with the goal of improving our understanding of the cellular signaling pathways associated with cortical GluN2B-containing NMDARs and determining their involvement in depression.

Public Health Relevance

The goal of these studies is to improve our understanding of the role that cortical n-methyl d- aspartate receptor (NMDAR)-mediated signaling plays in depression. The proposed experiments will better define the role of cortical GluN2B-containing NMDARs in regulating synapse function and behavior, while improving our understanding of how NMDAR antagonism produces its rapid antidepressant effects. Understanding these cellular mechanisms is critical for guiding pharmaceutical intervention in treatment-resistant depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH099378-01
Application #
8421361
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Nadler, Laurie S
Project Start
2013-03-15
Project End
2017-12-31
Budget Start
2013-03-15
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$327,770
Indirect Cost
$77,770
Name
Tulane University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Hou, Hailong; Chávez, Andrés E; Wang, Chih-Chieh et al. (2014) The Rac1 inhibitor NSC23766 suppresses CREB signaling by targeting NMDA receptor function. J Neurosci 34:14006-12