Prefrontal GABA(A)(δ)R Promotes Fear Extinction through Enabling the Plastic Regulation of Neuronal Intrinsic Excitability.

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABA(A) receptors (GABA(A)Rs). GABA(A)Rs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABA(A)Rs [GABA(A)(δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABA(A)R family. First, the fear extinction in individual mice was positively correlated with the level of GABA(A)(δ)R expression and function in their mPFC. Second, knockdown of GABA(A)(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABA(A)(δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABA(A)(δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABA(A)(δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABA(A)(δ)R had little influence on the extinction-evoked plasticity of glutamatergic transmission in these cells. Altogether, our findings revealed an unconventional and permissive role of extrasynaptic GABA(A) receptors in fear extinction through a route relying on nonsynaptic plasticity.SIGNIFICANCE STATEMENT The medial prefrontal cortex (mPFC) is one of the kernel brain regions engaged in fear extinction. Previous studies have repetitively shown that the GABA(A) receptor (GABA(A)R) family in this region act to suppress fear extinction. However, the roles of specific GABA(A)R subtypes in mPFC are largely unknown. We observed that the GABA(A)R-containing δ-subunit [GABA(A)(δ)R], a subtype of GABA(A)Rs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABA(A)R family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABA(A)Rs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABA(A)(δ)R promotes fear extinction through enabling the plastic regulation of neuronal excitability in the infralimbic subregion of mPFC. Our findings thus reveal an unconventional role of GABA(A)(δ)R in promoting fear extinction through a route relying on nonsynaptic plasticity.