Major depressive disorder (MDD) is a leading cause of total disability with inadequate treatment options and unresolved etiology. However, increasing evidence suggests that genetic and environmental vulnerabilities may converge on deficits of GABAergic transmission as a possible, causative core symptom of MDD. Other lines of research point to changes in glutamatergic transmission as being associated with MDD. In particular, subanesthetic doses of the NMDAR antagonist ketamin have rapid and lasting antidepressant effects even in otherwise drug-resistant forms of MDD, pointing to altered function of NMDA receptors. We have established GABA-A receptor gamma2 subunit heterozygous mice as an animal model with excellent construct, face and predictive validity of partially drug resistant MDD. Preliminary data show that GABA-A receptor deficits in gamma2 subunit heterozygous cultures result in markedly reduced expression and function of glutamate receptors. Treatment of mutant cultures with ketamine results in reversal of these deficits. Conversely, mice with GABA-A receptor deficit delimited to forebrain interneurons show a robust antidepressant-like phenotype. We here address the overall hypothesis that MDD is caused by reduced synaptic input from select subtypes of cortical and hippocampal GABAergic interneurons to pyramidal cells. The ensuing GABAergic deficit and altered E/I imbalance, through adaptive mechanisms results in reduced expression and function of ionotropic glutamate receptors, along with reduced functional connectivity of neurons. Transient treatment with NMDA receptor antagonists such as ketamine reverses these deficits and, following dissociation of the drug from the receptor, restores normal glutamatergic transmission. To address this hypothesis we will analyze ketamine-induced changes in expression and function of glutamate receptors and behavior in cultured neurons, brain slices and mice, respectively. We will further test whether chronic treatment with currently used antidepressants has similar effects on glutamatergic transmission. Lastly, we will use genetic deletion of the gamma2 subunit gene in small subsets of interneurons to identify interneuron subclasses that control depression-related behavior. Collectively, our proposal will contribute a major conceptual advance in understanding of the substrate of major depression as well as AD action.

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Major depressive disorder (MDD) is a leading cause of total disability with inadequate treatment options and unresolved etiology. We here take advantage of a genetically defined, GABAA receptor-deficient mouse model of MDD to experimentally test novel mechanisms of experimental and conventional antidepressant drugs and to genetically map the cell types that regulate depression-related behavior. These studies will provide a major conceptual advance in understanding of the molecular, cellular and pharmacological substrate regulating depression-related behavior.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Nadler, Laurie S
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Pennsylvania State University
Schools of Arts and Sciences
University Park
United States
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Fuchs, T; Jefferson, S J; Hooper, A et al. (2017) Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state. Mol Psychiatry 22:920-930
Du, Keyong; Murakami, Shoko; Sun, Yingmin et al. (2017) DHHC7 Palmitoylates Glucose Transporter 4 (Glut4) and Regulates Glut4 Membrane Translocation. J Biol Chem 292:2979-2991
Fuchs, T; Jefferson, S J; Hooper, A et al. (2017) Disinhibition of somatostatin-positive interneurons by deletion of postsynaptic GABAA receptors. Mol Psychiatry 22:787
Wang, Shaohui; Mott, Kevin R; Wawrowsky, Kolja et al. (2017) Binding of Herpes Simplex Virus 1 UL20 to GODZ (DHHC3) Affects Its Palmitoylation and Is Essential for Infectivity and Proper Targeting and Localization of UL20 and Glycoprotein K. J Virol 91:
Ren, Zhen; Pribiag, Horia; Jefferson, Sarah J et al. (2016) Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment. Biol Psychiatry 80:457-468
Leppä, Elli; Linden, Anni-Maija; Aller, Maria I et al. (2016) Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABAA Receptor ?2 Subunit in the Cerebellum. Front Pharmacol 7:403
Kilpatrick, Casey L; Murakami, Shoko; Feng, Mengyang et al. (2016) Dissociation of Golgi-associated DHHC-type Zinc Finger Protein (GODZ)- and Sertoli Cell Gene with a Zinc Finger Domain-? (SERZ-?)-mediated Palmitoylation by Loss of Function Analyses in Knock-out Mice. J Biol Chem 291:27371-27386
Ren, Zhen; Sahir, Nadia; Murakami, Shoko et al. (2015) Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice. Neuropharmacology 88:171-9
McBain, Chris J; Kittler, Josef; Luscher, Bernhard et al. (2015) GABAergic signaling in health and disease. Neuropharmacology 88:1
Ebersole, Brittany; Petko, Jessica; Woll, Matthew et al. (2015) Effect of C-Terminal S-Palmitoylation on D2 Dopamine Receptor Trafficking and Stability. PLoS One 10:e0140661

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