Major depressive disorder (MDD) is a devastating illness with broad socioeconomic effects. Although treatments for MDD have been available for nearly 50 years, available drugs are not always effective and require weeks or even months of treatment. The requirement for long-term antidepressant treatment (ADT) to achieve a therapeutic response has lead to the hypothesis that cellular and molecular adaptations are required. Our studies have characterized key adaptations in signal transduction and gene expression, most notably the cAMP-CREB and BDNF-ERK cascades, and we have begun to determine the functional responses at the behavioral and cellular levels to altered CREB and BDNF, The previous funding period has been productive and the results have contributed to a neurotrophic hypothesis of MDD and ADT that has stimulated a large body of clinical and preclinical studies. The research focus for the next funding period is a combination of extending these findings, as well as initiating new research areas, all of which are consistent with the NIMH Strategic Plan, In the first aim we will use conditional PDE4A mutant mice that we have generated, the first for any PDE4 subtype, to determine if PDE4A is a viable target for novel antidepressant medications that activate the cAMP-CREB cascade. We will utilize a battery of behavioral models, including anxiety, despair, anhedonia, and motivation/reward to assess the phenotype of these animals, and custom microarrays to identify additional downstream gene targets. In the second aim we will use a similar strategy to determine if MKP-1, a dual specificity phosphatase that we have found is increased in MDD patients, is a viable target for development of drugs that activate the BDNF-ERK cascade. Preliminary studies demonstrate that MKP-1 mutant mice are resistant to chronic stress, suggesting that increased MKP-1 expression would increase susceptibility to MDD.
The third aim will characterize additional neurotrophic factor regulated gene targets in cellular and behavioral models of MDD. We will also characterize common promoter elements that control cassettes of genes involved in MDD and ADT response, including neuroplasticity, neuroprotection, and synaptic function/formation.

Public Health Relevance

(See Instructions): These studies will further characterize the mechanisms underlying the action of ADT as well as the deleterious effects of stress and identify novel drug targets for the development of faster acting and more efficacious medications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH045481-24
Application #
8442920
Study Section
Special Emphasis Panel (NSS)
Program Officer
Nadler, Laurie S
Project Start
1989-09-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
24
Fiscal Year
2013
Total Cost
$336,204
Indirect Cost
$98,604
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Duman, Ronald S; Aghajanian, George K; Sanacora, Gerard et al. (2016) Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 22:238-49
Lepack, Ashley E; Bang, Eunyoung; Lee, Boyoung et al. (2016) Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures. Neuropharmacology 111:242-252
Wohleb, Eric S; Wu, Min; Gerhard, Danielle M et al. (2016) GABA interneurons mediate the rapid antidepressant-like effects of scopolamine. J Clin Invest 126:2482-94
Liu, Rong-Jian; Duman, Catharine; Kato, Taro et al. (2016) GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine. Neuropsychopharmacology :
Wu, Melody V; Sahay, Amar; Duman, Ronald S et al. (2015) Functional differentiation of adult-born neurons along the septotemporal axis of the dentate gyrus. Cold Spring Harb Perspect Biol 7:a018978
Liu, Rong-Jian; Ota, Kristie T; Dutheil, Sophie et al. (2015) Ketamine Strengthens CRF-Activated Amygdala Inputs to Basal Dendrites in mPFC Layer V Pyramidal Cells in the Prelimbic but not Infralimbic Subregion, A Key Suppressor of Stress Responses. Neuropsychopharmacology 40:2066-75
Ota, Kristie T; Andres, Wells; Lewis, David A et al. (2015) BICC1 expression is elevated in depressed subjects and contributes to depressive behavior in rodents. Neuropsychopharmacology 40:711-8
Fuchikami, Manabu; Thomas, Alexandra; Liu, Rongjian et al. (2015) Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions. Proc Natl Acad Sci U S A 112:8106-11
Duman, Ronald S; Aghajanian, George K (2014) Neurobiology of rapid acting antidepressants: role of BDNF and GSK-3*. Neuropsychopharmacology 39:233
Ota, Kristie T; Liu, Rong-Jian; Voleti, Bhavya et al. (2014) REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nat Med 20:531-5

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