Depression is a debilitating and recurring psychiatric disorder. Approximately half of the patients with depressive disorder fail to respond to currently available antidepressants. The long-term goal of this project is to understand the pathogenesis of depressive disorders and to develop new therapeutic approaches for this disease. This is a resubmission of the application for competitive renewal of our current funding to study the molecular and cellular mechanisms underlying the antidepressant-like effect of the adipocyte- derived hormone, leptin. We have provided strong evidence that leptin possesses antidepressant-like properties, supporting a new adipostatic hypothesis of depression. Direct infusion of leptin into the hippocampus produces antidepressant-like effects, and ablation of the functional leptin receptor, LepRb, in this brain region induces depressive-like behaviors, suggesting an essential role of LepRb in the hippocampus in mediating leptin action on depressive behaviors. We have made novel observations that ablation of LepRb principally in forebrain glutamatergic neurons (Lepr cKO) leads to depressive-like symptoms and facilitates NMDA-induced synaptic depression in the hippocampus. The antidepressant-like behavioral effects of leptin were abolished in Lepr cKO mice. These mice were resistant to selective serotonin reuptake inhibitor (SSRI) treatments but highly responsive to the glutamate receptor NMDA- NR2B (also termed GluN2B) antagonist. These findings led to the hypothesis that the glutamatergic system mediates leptin action on depressive behaviors. We propose to determine 1) the role of hippocampal glutamate neurotransmission in mediating the antidepressant-like effects of leptin, and 2) the contribution of remodeling of hippocampal dendritic spines, sites of glutamatergic synapses, to the antidepressant-like effects of leptin. These studies will generate novel insights into molecular and cellular mechanisms into leptin action in the limbic system and lead to the development of novel therapies for depression.

Public Health Relevance

Major depression is a severe and recurrent mental illness that is highly prevalent worldwide. Currently available antidepressant drugs are only effective in a subset of patients, and the onset of therapeutic actions requires weeks to months of treatment. The goals of this research project are to understand the mechanisms of the pathophysiology and pathogenesis of depression-related behaviors and to identify novel molecular and neural targets for treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH076929-07
Application #
8544491
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Winsky, Lois M
Project Start
2006-04-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
7
Fiscal Year
2013
Total Cost
$320,678
Indirect Cost
$104,678
Name
University of Texas Health Science Center San Antonio
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Wang, X; Zhang, D; Lu, X-Y (2015) Dentate gyrus-CA3 glutamate release/NMDA transmission mediates behavioral despair and antidepressant-like responses to leptin. Mol Psychiatry 20:509-19
Liu, Jing; Garza, Jacob C; Li, Wei et al. (2013) Melanocortin-4 receptor in the medial amygdala regulates emotional stress-induced anxiety-like behaviour, anorexia and corticosterone secretion. Int J Neuropsychopharmacol 16:105-20
Guo, Ming; Huang, Tung-Yi; Garza, Jacob C et al. (2013) Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours. Int J Neuropsychopharmacol 16:857-67
Guo, Ming; Lu, Yuan; Garza, Jacob C et al. (2012) Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression. Transl Psychiatry 2:e83
Zhang, Di; Guo, Ming; Zhang, Wei et al. (2011) Adiponectin stimulates proliferation of adult hippocampal neural stem/progenitor cells through activation of p38 mitogen-activated protein kinase (p38MAPK)/glycogen synthase kinase 3ýý (GSK-3ýý)/ýý-catenin signaling cascade. J Biol Chem 286:44913-20
Yu, Tao; Guo, Ming; Garza, Jacob et al. (2011) Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction. Int J Neuropsychopharmacol 14:303-17
Liu, J; Perez, S M; Zhang, W et al. (2011) Selective deletion of the leptin receptor in dopamine neurons produces anxiogenic-like behavior and increases dopaminergic activity in amygdala. Mol Psychiatry 16:1024-38
Liu, Jing; Garza, Jacob C; Bronner, Jamaur et al. (2010) Acute administration of leptin produces anxiolytic-like effects: a comparison with fluoxetine. Psychopharmacology (Berl) 207:535-45
Garza, Jacob C; Kim, Chung Sub; Liu, Jing et al. (2008) Adeno-associated virus-mediated knockdown of melanocortin-4 receptor in the paraventricular nucleus of the hypothalamus promotes high-fat diet-induced hyperphagia and obesity. J Endocrinol 197:471-82
Garza, Jacob C; Guo, Ming; Zhang, Wei et al. (2008) Leptin increases adult hippocampal neurogenesis in vivo and in vitro. J Biol Chem 283:18238-47

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