Extrasynaptic GABAA 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 delta-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.