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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. [ABSTRACT FROM AUTHOR]

Both human and experimental evidence strongly supports the view of brain region- and cell-specific changes in tonic GABA inhibition in temporal lobe epilepsies ( TLE). This 'tonic' form of signalling is not time-locked to presynaptic action potentials, which depends upon detection of ambient GABA by extrasynaptic GABAA receptors ( GABAARs). Extrasynaptic GABAARs have distinct physiological and pharmacological features, including high GABA-binding affinity and low desensitization and a variety of the specific subunit combinations (α4δ-,α6δ-,α5γ-,ε-containing receptors). These features closely contribute to the function of tonic GABA current, which is preserved properly or increased in dentate gyrus in models of TLE, even in the face of a loss of synaptic inhibition and inhibitory interneurones. Markedly reduced tonic GABA inhibition may facilitate an episode of epilepsy, while persistent elevated tonic inhibition may contribute to the onset of spontaneous recurrent seizures. In dentate granule cells, tonic GABA inhibition is positively modulated by endogenous neurosteroids and other factors, which undergo changes related to hormonal status after TLE. Tonic inhibition regulates neuronal excitability through its effects on membrane potential by both offsetting the threshold and reducing the frequency of action potentials and input resistance. Therefore, extrasynaptic GABAARs are expected to be the most important pharmacological targets in TLE. It is likely that both elevate the ambient GABA concentration and potentiate the tonic currents, contributing to the antiepileptic effects. [ABSTRACT FROM AUTHOR]