This is an application for funding of a study examining the neurobiology of fear and anxiety with a special emphasis on the role of synaptic ?2-containing GABAA receptors and extrasynaptic ?5- containing GABAA receptors. The ?2-containing GABAA receptors, which have been shown to mediate the anxiolytic-like action of diazepam in ethological tests of anxiety will be deleted from hippocampal principal neurons in the CA1, CA3, and DG subregions, respectively, and from the basolateral amygdala using cre- loxP-mediated recombination to elucidate subregion-specific functions and neuronal circuits (e.g. hippocampal trisynaptic and monosynaptic pathways) involved in modulation of anxiety. While the function of neurons in defined hippocampal subregions in learning and memory tasks has been extensively studied, the functions of these neurons in the regulation of emotions is still unknown. Preliminary results indicate a role for extrasynaptic ?5-containing GABAA receptors in extinction of conditioned fear, and based on this observation we propose experiments directed towards the development of a novel therapeutic strategy to promote extinction, which is a major goal in the treatment of posttraumatic stress disorder. Anxiety disorders are the most prevalent type of psychiatric disorders in the community, affecting approximately 10%-15% of the population. This proposal will investigate the functional role of GABAA receptor subtypes in defined neuronal circuits in the hippocampus and the amygdala for the modulation of anxiety-related behaviors. It is expected that the proposed research will identify the ?2- and the ?5- containing GABAA receptors as separate molecular targets for the treatment of distinct anxiety disorders, e.g. generalized anxiety disorder and posttraumatic stress disorder.

Public Health Relevance

Anxiety disorders are the most prevalent type of psychiatric disorders in the community, affecting approximately 10%-15% of the population. This proposal will investigate the functional role of GABAA receptor subtypes in defined neuronal circuits in the hippocampus and the amygdala for the modulation of anxiety-related behaviors. It is expected that the proposed research will identify the ?2- and the ?5- containing GABAA receptors as separate molecular targets for the treatment of distinct anxiety disorders, e.g. generalized anxiety disorder and posttraumatic stress disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH080006-05
Application #
8489338
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Winsky, Lois M
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$375,408
Indirect Cost
$137,808
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Deprez, Francine; Vogt, Fabia; Floriou-Servou, Amalia et al. (2016) Partial inactivation of GABAA receptors containing the ?5 subunit affects the development of adult-born dentate gyrus granule cells. Eur J Neurosci 44:2258-71
Newman, Emily L; Gunner, Georgia; Huynh, Polly et al. (2016) Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge-Like and Blunted Chronic Drinking by Mice. Alcohol Clin Exp Res 40:2445-2455
Engin, Elif; Smith, Kiersten S; Gao, Yudong et al. (2016) Modulation of anxiety and fear via distinct intrahippocampal circuits. Elife 5:e14120
Engin, Elif; Zarnowska, Ewa D; Benke, Dietmar et al. (2015) Tonic Inhibitory Control of Dentate Gyrus Granule Cells by ?5-Containing GABAA Receptors Reduces Memory Interference. J Neurosci 35:13698-712
Botta, Paolo; Demmou, Lynda; Kasugai, Yu et al. (2015) Regulating anxiety with extrasynaptic inhibition. Nat Neurosci 18:1493-500
Newman, Emily L; Smith, Kiersten S; Takahashi, Aki et al. (2015) ?2-containing GABA(A) receptors: a requirement for midazolam-escalated aggression and social approach in mice. Psychopharmacology (Berl) 232:4359-69
Vien, Thuy N; Modgil, Amit; Abramian, Armen M et al. (2015) Compromising the phosphodependent regulation of the GABAAR ?3 subunit reproduces the core phenotypes of autism spectrum disorders. Proc Natl Acad Sci U S A 112:14805-10
Rudolph, Uwe; Möhler, Hanns (2014) GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. Annu Rev Pharmacol Toxicol 54:483-507
Benham, Rebecca S; Engin, Elif; Rudolph, Uwe (2014) Diversity of neuronal inhibition: a path to novel treatments for neuropsychiatric disorders. JAMA Psychiatry 71:91-3
Engin, Elif; Bakhurin, Konstantin I; Smith, Kiersten S et al. (2014) Neural basis of benzodiazepine reward: requirement for ?2 containing GABAA receptors in the nucleus accumbens. Neuropsychopharmacology 39:1805-15

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