| First Author | Gafford GM | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 40 | Pages | 16330-5 |
| PubMed ID | 22992651 | Mgi Jnum | J:190101 |
| Mgi Id | MGI:5448077 | Doi | 10.1073/pnas.1119261109 |
| Citation | Gafford GM, et al. (2012) Cell-type specific deletion of GABA(A)alpha1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction. Proc Natl Acad Sci U S A 109(40):16330-5 |
| abstractText | 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)alpha1 subunits specifically from CRF neurons [CRF-GABA(A)alpha1 KO]. This process resulted in mice with decreased GABA(A)alpha1 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)alpha1 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)alpha1-preferring benzodiazepine-site agonist, into the BNST of the CRF-GABA(A)alpha1 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)alpha1 neurons causes increased anxiety and impaired fear extinction, both of which are symptoms diagnostic for anxiety disorders, such as posttraumatic stress disorder. |
