Laboratory of Fear and Anxiety Disorders, Institutes of Life Science, Nanchang University, Nanchang 330031, People's Republic of China.
Department of Biological Science, School of Life Sciences, Nanchang University, Nanchang 330031, People's Republic of China.
J Neurosci. 2022 Jul 20;42(29):5755-5770. doi: 10.1523/JNEUROSCI.0689-22.2022. Epub 2022 Jun 15.
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 receptors (GABARs). GABARs 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 GABARs [GABA(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 GABAR family. First, the fear extinction in individual mice was positively correlated with the level of GABA(δ)R expression and function in their mPFC. Second, knockdown of GABA(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABA(δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABA(δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABA(δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABA(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 receptors in fear extinction through a route relying on nonsynaptic plasticity. The medial prefrontal cortex (mPFC) is one of the kernel brain regions engaged in fear extinction. Previous studies have repetitively shown that the GABA receptor (GABAR) family in this region act to suppress fear extinction. However, the roles of specific GABAR subtypes in mPFC are largely unknown. We observed that the GABAR-containing δ-subunit [GABA(δ)R], a subtype of GABARs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABAR family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABARs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABA(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(δ)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适应不断变化的环境至关重要，这个过程需要 GABA 受体（GABARs）的参与。GABARs 由数十种结构、药理学和功能上不同的亚型组成。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，在调节情绪的核心区域——内侧前额叶皮层（mPFC）中，位于突触外的 δ 亚基 GABA 受体[GABA(δ)Rs]，在调节雄性小鼠的恐惧消退中具有允许作用，这一作用与整个 GABAR 家族的抑制作用形成鲜明对比。首先，个体小鼠的恐惧消退与它们 mPFC 中 GABA(δ)R 的表达和功能水平呈正相关。其次，mPFC 中的 GABA(δ)R 敲低，特别是在其下边缘（IL）亚区，足以损害小鼠的恐惧消退。第三，GABA(δ)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(δ)R 可挽救受损的消退。进一步的机制研究表明，GABA(δ)R 的允许作用与其在允许 IL 投射神经元中兴奋性的、由消退引发的可塑性调节中的作用有关。相比之下，GABA(δ)R 对这些细胞中谷氨酸能传递的由消退引发的可塑性几乎没有影响。总的来说，我们的研究结果揭示了突触外 GABA 受体在恐惧消退中的一种非传统的允许作用，通过一种依赖于非突触可塑性的途径。内侧前额叶皮层（mPFC）是参与恐惧消退的核心脑区之一。先前的研究反复表明，该区域的 GABA 受体（GABAR）家族通过抑制恐惧消退起作用。然而，mPFC 中特定 GABAR 亚型的作用在很大程度上是未知的。我们观察到 GABA 受体包含的 δ 亚基[GABA(δ)R]，GABARs 的一种亚型，专门位于突触外膜上，介导紧张性神经元抑制，与整个 GABAR 家族作用相反，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由消退引发的可塑性来抑制恐惧消退的突触 GABARs 形成鲜明对比的是，GABA(δ)R 通过使 mPFC 的下边缘亚区的神经元兴奋性的可塑性调节，促进恐惧消退。因此，我们的研究结果揭示了 GABA(δ)R 通过依赖非突触可塑性的途径促进恐惧消退的一种非传统作用。
