Prefrontal GABAA(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, 6-subunit-containing GABA(A)Rs [GABA(A)(delta)R], 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)(delta)R expression and function in their mPFC. Second, knockdown of GABA(A)(delta)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GGABA(A)(delta)R-deficient mice also showed fear extinction deficits, and re-expressing GABA(A)(delta)R in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABA(A)(delta)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABA(A)(delta)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.