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_ARs). GABA_ARs 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, -subunit-containing GABA_ARs [GABA_A()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_AR family. First, the fear extinction in individual mice was positively correlated with the level of GABA_A()R expression and function in their mPFC. Second, knockdown of GABA_A()R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABA_A()R-deficient mice also showed fear extinction deficits, and re-expressing GABA_A()Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABA_A()R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABA_A()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_AR) family in this region act to suppress fear extinction. However, the roles of specific GABA_AR subtypes in mPFC are largely unknown. We observed that the GABA_AR-containing -subunit [GABA_A()R], a subtype of GABA_ARs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABA_AR family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABA_ARs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABA_A()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()R in promoting fear extinction through a route relying on nonsynaptic plasticity.

消除先前获得的恐惧对于生物体适应不断变化的环境至关重要，这一过程需要 GABA _A受体 (GABA _A Rs) 的参与。GABA ARS_由数十种结构、药理学和功能异质的亚型组成。然而，这些亚型在恐惧消退中的具体作用在很大程度上仍未得到探索。在这里，我们观察到在内侧前额叶皮层 (mPFC)，情绪调节的核心区域，位于突触外的，含有 γ-亚基的 GABA _A Rs [GABA _A ()Rs]，在调节男性恐惧消退方面具有许可作用小鼠，这种效果与整个 GABA _A既定但抑制的作用形成鲜明对比R家族。_{首先，个体小鼠的恐惧消退与其 mPFC 中的 GABA A} ()R 表达和功能水平呈正相关。其次，敲低mPFC中的 GABA _{A ()R，特别是在边缘下 (IL) 亚区域，足以削弱小鼠的恐惧消退。}第三，GABA _A ()R 缺陷小鼠也表现出恐惧消退缺陷，并且在这些小鼠的 IL 中重新表达 GABA _{A ()Rs 可以挽救受损的消退。}进一步的机制研究表明，GABA _A ()R 的允许效应与其在 IL 投射神经元中实现神经元兴奋性的消退诱发塑性调节中的作用相关。相比之下，GABA _A()R 对这些细胞中谷氨酸能传递的消退诱发可塑性几乎没有影响。总而言之，我们的研究结果揭示了突触外 GABA _A受体通过依赖非突触可塑性的途径在恐惧消退中的非常规和许可作用。

意义声明内侧前额叶皮层 (mPFC) 是参与恐惧消退的核心大脑区域之一。先前的研究反复表明，该区域的 GABA _A受体 (GABA _A R) 家族可抑制恐惧消退。然而，特定 GABA _A R 亚型在 mPFC 中的作用在很大程度上是未知的。我们观察到含有 GABA _A R 的亚基 [GABA _{A ()R] 是 GABA A} Rs的一种亚型，专门位于突触外膜并介导强直神经元抑制，其作用与整个 GABA _A相反R 家族促进（但不抑制）恐惧消退。更有趣的是，与通过破坏谷氨酸能传递的消退诱发的可塑性来抑制恐惧消退的突触 GABA _A Rs形成鲜明对比的是，GABA _A () R 通过启用 mPFC 边缘下亚区神经元兴奋性的塑性调节来促进恐惧消退. 因此，我们的研究结果揭示了 GABA _A ()R 在通过依赖非突触可塑性的途径促进恐惧消退方面的非常规作用。