Extrasynaptic GABAA receptors in mediodorsal thalamic nucleus modulate fear extinction learning
Open accessAbstract
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.
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Selective knockdown of α4GABAARs in the mediodorsal thalamic nucleus recapitulates the effect of gabazine on fear extinction.
“The effect of gabazine on fear extinction was recapitulated by a selective knockdown of α4GABAARs in the mediodorsal thalamic nucleus [92].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [92]
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- Authors
- Paydar, A., Lee, B., Gangadharan, G., Lee, S., Hwang, E. M., & Shin, H.-S.
- Affiliations
- Institute for Basic Science (KR)
- Korea Institute of Science and Technology (KR)
- Corresponding author
- Shin, Hee-Sup
- Venue
- Molecular Brain
- Published
- 2014-05-29
- Volume
- 7
- Issue
- 1
- Pages
- 39-39
- ISSN
- 1756-6606 (ISSN-L)
- PMC
- PMC4066285
- OpenAlex
- W2136046691
- Cited by
- 37
- References
- 42
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 4 · 2023: 4 · 2022: 1 · 2021: 5 · 2020: 1 · 2019: 1 · 2018: 4 · 2017: 1 · 2016: 1 · 2015: 4 · 2014: 1
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Yale University
- Korea Institute of Science and Technology
- Institute for Basic Science (IBS-R001, IBS-R001-D1)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- extrasynaptic GABAA receptors, mediodorsal thalamus, fear extinction, delta subunit, gabazine, THIP, fear conditioning, anxiety disorders, post-traumatic stress disorder, freezing behavior
- MeSH terms
- Animals, Extinction, Psychological, Fear, Isoxazoles, Male, Pyridazines, Receptors, GABA-A, Synapses, Transfection, Mice, Knockout, Integrases, Mediodorsal Thalamic Nucleus, Mice
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