title: Cell-type specific deletion of GABA(A)α1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction.
abstract: 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.
authors.affiliation: Center for Behavioral Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA 30329, USA.
authors.forename: Georgette M
authors.initials: GM
authors.lastname: Gafford
authors.forename: Ji-Dong
authors.initials: JD
authors.lastname: Guo
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Flandreau
authors.forename: Rimi
authors.initials: R
authors.lastname: Hazra
authors.forename: Donald G
authors.initials: DG
authors.lastname: Rainnie
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology*; D003213:Conditioning, Psychological / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011725:Pyridines; D011743:Pyrimidines; D011963:Receptors, GABA-A / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077334:Zolpidem
chemical_list: D017931:DNA Primers; D011725:Pyridines; D011743:Pyrimidines; C412383:R 121919; D011963:Receptors, GABA-A; D000077334:Zolpidem; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone