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Author Notes:

To whom correspondence should be addressed. E-mail: kressle@emory.edu.

Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved August 24, 2012 (received for review November 22, 2011)

Author contributions: G.M.G., D.G.R., and K.J.R. designed research; G.M.G., J.-D.G., and R.H. performed research; G.M.G., E.I.F., and K.J.R. contributed new reagents/analytic tools; G.M.G., J.-D.G., R.H., D.G.R., and K.J.R. analyzed data; and G.M.G., D.G.R., and K.J.R. wrote the paper.


Research Funding:

Support was provided by the National Institutes of Health (Grants DA019624 and F32MH090785), the National Science Foundation (GRFP DGE-0234618), the Burroughs Wellcome Fund, and National Institutes of Health/National Center for Research Resources base Grant P51RR000165 (to the Yerkes National Primate Research Center).


  • central amygdala
  • plasticity
  • HPA axis
  • short term synaptic depression
  • knockout

Cell-type specific deletion of GABA(A)α1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction


Journal Title:

Proceedings of the National Academy of Sciences


Volume 109, Number 40


, Pages 16330-16335

Type of Work:

Article | Post-print: After Peer Review


Corticotropin-releasing factor (CRF) is critical for the endocrine, autonomic, and behavioral responses to stressors, and it has been shown to modulate fear and anxiety. The CRF receptor is widely expressed across a variety of cell types, impeding progress toward understanding the contribution of specific CRF-containing neurons to fear dysregulation. We used a unique CRF-Cre driver transgenic mouse line to remove floxed GABA(A)α1 subunits specifically from CRF neurons [CRF-GABA(A)α1 KO]. This process resulted in mice with decreased GABA(A)α1 expression only in CRF neurons and increased CRF mRNA within the amygdala, bed nucleus of the stria terminalis (BNST) and paraventricular nucleus of the hypothalamus. These mice show normal locomotor and pain responses and no difference in depressive-like behavior or Pavlovian fear conditioning. However, CRF-GABA(A)α1 KO increased anxiety-like behavior and impaired extinction of conditioned fear, coincident with an increase in plasma corticosterone concentration. These behavioral impairments were rescued with systemic or BNST infusion of the CRF antagonist R121919. Infusion of Zolpidem, a GABA(A)α1-preferring benzodiazepine-site agonist, into the BNST of the CRF-GABA(A)α1 KO was ineffective at decreasing anxiety. Electrophysiological findings suggest a disruption in inhibitory current may play a role in these changes. These data indicate that disturbance of CRF containing GABA(A)α1 neurons causes increased anxiety and impaired fear extinction, both of which are symptoms diagnostic for anxiety disorders, such as posttraumatic stress disorder.

Copyright information:

Beginning with articles submitted in Volume 106 (2009) the author(s) retains copyright to individual articles, and the National Academy of Sciences of the United States of America retains an exclusive license to publish these articles and holds copyright to the collective work.

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