Trait anxiety describes a personality trait characterized by an elevated basal level of anxiety that represents a vulnerability factor for anxiety disorders and various forms of depression. Anxiety-disorders that afflict humans include generalized anxiety disorder (GAD), panic, diverse phobias and posttraumatic stress disorder (PTSD) which, together, are among the most frequent and costly psychiatric illnesses. The longterm goal of our research is to elucidate the molecular and cellular mechanisms underlying anxiety disorders. GABA-A receptors are widely recognized to hold a gatekeeper function in the modulation of anxiety state, especially in GAD and panic disorder. Mice with a heterozygous mutation of the GABA-A receptor gamma 2 subunit gene have been established as an animal model of that anxiety that exbits behavioral and cogntive deficits reminiscent of GAD in humans. Conditional deletion of this gene in pyramidal forebrain neurons during embryogenesis but not in adolescent mice leads to excessive trait anxiety in adults. In agreement with a developmental mechanism underlying trait anxiety, gamma 2 subunit heterozygous mice exhibit reduced hippocampal neurogenesis and serotonergic transmission. Based on these observations we hypothesize (I) that trait anxiety is due to the loss of specific types of hippocampal neurons during development. We further hypothesize (II) that the GABA-A receptor deficit leads to a deficit in serotonergic transmission that contributes to the manifestation of trait anxiety. We also predict (III) that treatment of young mutant mice with antidepressant and neurogenesis-enhancing drugs prevents development of trait anxiety in adults. Finally, (IV) we hypothesize that GABA-A receptor deficits in the hippocampus and cerebral cortex act independently of deficits in the amygdala to establish an anxiety-like phenotype. Together these studies will greatly advance our undestanding of the mechanism underlying anxiety and depressive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH060989-05
Application #
7058245
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Winsky, Lois M
Project Start
1999-12-01
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
5
Fiscal Year
2006
Total Cost
$309,005
Indirect Cost
Name
Pennsylvania State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Shen, Qiuying; Fuchs, Thomas; Sahir, Nadia et al. (2012) GABAergic control of critical developmental periods for anxiety- and depression-related behavior in mice. PLoS One 7:e47441
Luscher, B; Shen, Q; Sahir, N (2011) The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 16:383-406
Luscher, Bernhard; Fuchs, Thomas; Kilpatrick, Casey L (2011) GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron 70:385-409
Luscher, Bernhard; Shen, Qiuying (2011) Gamma-aminobutyric acidergic deficits cause melancholic depression: a reply to Markou and Geyer. Biol Psychiatry 69:e13-4; author reply e15-6
Shen, Qiuying; Lal, Rachnanjali; Luellen, Beth A et al. (2010) gamma-Aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression. Biol Psychiatry 68:512-20
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Yuan, Xu; Yao, Jun; Norris, David et al. (2008) Calcium-modulating cyclophilin ligand regulates membrane trafficking of postsynaptic GABA(A) receptors. Mol Cell Neurosci 38:277-89
Earnheart, John C; Schweizer, Claude; Crestani, Florence et al. (2007) GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J Neurosci 27:3845-54
Fang, Cheng; Deng, Lunbin; Keller, Cheryl A et al. (2006) GODZ-mediated palmitoylation of GABA(A) receptors is required for normal assembly and function of GABAergic inhibitory synapses. J Neurosci 26:12758-68
Sinkkonen, Saku T; Luscher, Bernhard; Luddens, Hartmut et al. (2004) Autoradiographic imaging of altered synaptic alphabetagamma2 and extrasynaptic alphabeta GABAA receptors in a genetic mouse model of anxiety. Neurochem Int 44:539-47

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