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 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.