title: Extrasynaptic GABAA receptors in mediodorsal thalamic nucleus modulate fear extinction learning.
abstract: BACKGROUND
  The gamma-amino-butyric acid (GABA) system is a critical mediator of fear extinction process. GABA can induce "phasic" or "tonic" inhibition in neurons through synaptic or extrasynaptic GABAA receptors, respectively. However, role of the thalamic "tonic GABA inhibition" in cognition has not been explored. We addressed this issue in extinction of conditioned fear in mice.
  
  
  RESULTS
  Here, we show that GABAA receptors in the mediodorsal thalamic nucleus (MD) modulate fear extinction. Microinjection of gabazine, a GABAA receptor antagonist, into the MD decreased freezing behavior in response to the conditioned stimulus and thus facilitated fear extinction. Interestingly, microinjection of THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a preferential agonist for the δ-subunit of extrasynaptic GABAA receptors, into the MD attenuated fear extinction. In the opposite direction, an MD-specific knock-out of the extrasynaptic GABAA receptors facilitated fear extinction.
  
  
  CONCLUSIONS
  Our results suggest that "tonic GABA inhibition" mediated by extrasynaptic GABAA receptors in MD neurons, suppresses fear extinction learning. These results raise a possibility that pharmacological control of tonic mode of GABAA receptor activation may be a target for treatment of anxiety disorders like post-traumatic stress disorder.
authors.forename: Afshin
authors.initials: A
authors.lastname: Paydar
authors.forename: Boyoung
authors.initials: B
authors.lastname: Lee
authors.forename: Gireesh
authors.initials: G
authors.lastname: Gangadharan
authors.forename: Sukchan
authors.initials: S
authors.lastname: Lee
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Hwang
authors.affiliation: Center for Cognition and Sociality, Institute for Basic Science (IBS), 70, Yusung-daero 1689-gil, Yusung-gu, Daejeon 305-811, Republic of Korea. shin@ibs.re.kr.
authors.forename: Hee-Sup
authors.initials: HS
authors.lastname: Shin
mesh_terms: D000818:Animals; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D020645:Mediodorsal Thalamic Nucleus / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000172:deficiency / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection
chemical_list: C546261:Gabra4 protein, mouse; D007555:Isoxazoles; D011724:Pyridazines; D011963:Receptors, GABA-A; C049853:gabazine; C045073:Cre recombinase; D019426:Integrases; C015542:gaboxadol