Cargando…

Extrasynaptic GABA(A) receptors in mediodorsal thalamic nucleus modulate fear extinction learning

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 GABA(A) receptors, respectively. However, role of the thalamic “tonic GABA inhibition” in cognition ha...

Descripción completa

Detalles Bibliográficos
Autores principales: Paydar, Afshin, Lee, Boyoung, Gangadharan, Gireesh, Lee, Sukchan, Hwang, Eun Mi, Shin, Hee-Sup
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066285/
https://www.ncbi.nlm.nih.gov/pubmed/24886120
http://dx.doi.org/10.1186/1756-6606-7-39
_version_ 1782322161875156992
author Paydar, Afshin
Lee, Boyoung
Gangadharan, Gireesh
Lee, Sukchan
Hwang, Eun Mi
Shin, Hee-Sup
author_facet Paydar, Afshin
Lee, Boyoung
Gangadharan, Gireesh
Lee, Sukchan
Hwang, Eun Mi
Shin, Hee-Sup
author_sort Paydar, Afshin
collection PubMed
description 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 GABA(A) 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 GABA(A) receptors in the mediodorsal thalamic nucleus (MD) modulate fear extinction. Microinjection of gabazine, a GABA(A) 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 GABA(A) receptors, into the MD attenuated fear extinction. In the opposite direction, an MD-specific knock-out of the extrasynaptic GABA(A) receptors facilitated fear extinction. CONCLUSIONS: Our results suggest that “tonic GABA inhibition” mediated by extrasynaptic GABA(A) receptors in MD neurons, suppresses fear extinction learning. These results raise a possibility that pharmacological control of tonic mode of GABA(A) receptor activation may be a target for treatment of anxiety disorders like post-traumatic stress disorder.
format Online
Article
Text
id pubmed-4066285
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-40662852014-06-24 Extrasynaptic GABA(A) receptors in mediodorsal thalamic nucleus modulate fear extinction learning Paydar, Afshin Lee, Boyoung Gangadharan, Gireesh Lee, Sukchan Hwang, Eun Mi Shin, Hee-Sup Mol Brain Research 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 GABA(A) 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 GABA(A) receptors in the mediodorsal thalamic nucleus (MD) modulate fear extinction. Microinjection of gabazine, a GABA(A) 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 GABA(A) receptors, into the MD attenuated fear extinction. In the opposite direction, an MD-specific knock-out of the extrasynaptic GABA(A) receptors facilitated fear extinction. CONCLUSIONS: Our results suggest that “tonic GABA inhibition” mediated by extrasynaptic GABA(A) receptors in MD neurons, suppresses fear extinction learning. These results raise a possibility that pharmacological control of tonic mode of GABA(A) receptor activation may be a target for treatment of anxiety disorders like post-traumatic stress disorder. BioMed Central 2014-05-29 /pmc/articles/PMC4066285/ /pubmed/24886120 http://dx.doi.org/10.1186/1756-6606-7-39 Text en Copyright © 2014 Paydar et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Paydar, Afshin
Lee, Boyoung
Gangadharan, Gireesh
Lee, Sukchan
Hwang, Eun Mi
Shin, Hee-Sup
Extrasynaptic GABA(A) receptors in mediodorsal thalamic nucleus modulate fear extinction learning
title Extrasynaptic GABA(A) receptors in mediodorsal thalamic nucleus modulate fear extinction learning
title_full Extrasynaptic GABA(A) receptors in mediodorsal thalamic nucleus modulate fear extinction learning
title_fullStr Extrasynaptic GABA(A) receptors in mediodorsal thalamic nucleus modulate fear extinction learning
title_full_unstemmed Extrasynaptic GABA(A) receptors in mediodorsal thalamic nucleus modulate fear extinction learning
title_short Extrasynaptic GABA(A) receptors in mediodorsal thalamic nucleus modulate fear extinction learning
title_sort extrasynaptic gaba(a) receptors in mediodorsal thalamic nucleus modulate fear extinction learning
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066285/
https://www.ncbi.nlm.nih.gov/pubmed/24886120
http://dx.doi.org/10.1186/1756-6606-7-39
work_keys_str_mv AT paydarafshin extrasynapticgabaareceptorsinmediodorsalthalamicnucleusmodulatefearextinctionlearning
AT leeboyoung extrasynapticgabaareceptorsinmediodorsalthalamicnucleusmodulatefearextinctionlearning
AT gangadharangireesh extrasynapticgabaareceptorsinmediodorsalthalamicnucleusmodulatefearextinctionlearning
AT leesukchan extrasynapticgabaareceptorsinmediodorsalthalamicnucleusmodulatefearextinctionlearning
AT hwangeunmi extrasynapticgabaareceptorsinmediodorsalthalamicnucleusmodulatefearextinctionlearning
AT shinheesup extrasynapticgabaareceptorsinmediodorsalthalamicnucleusmodulatefearextinctionlearning