Maintaining appropriate levels of fear memory specificity is crucial for individual’s survival and mental health, whereas overgeneralized fear commonly occurs in neuropsychiatric disorders, including posttraumatic stress disorder and generalized anxiety disorder. However, the molecular mechanisms regulating fear memory specificity remain poorly understood. The medial prefrontal cortex (mPFC) is considered as a key brain region in fear memory regulation. Previous transcriptomic studies have identified that plexin-A1, a transmembrane receptor critical for axon development, was downregulated in the mPFC after fear memory training. In this study, we identified that learning-induced downregulation of the mRNA and protein levels of plexin-A1 specifically occurred in the inhibitory but not excitatory neurons in the infralimbic cortex (IL) of mPFC. Further studies of plexin-A1 by virus-mediated over-expression of functional mutants selectively in the IL inhibitory neurons revealed the critical roles of plexin-A1 for regulating memory specificity and anxiety. Moreover, our findings revealed that plexin-A1 regulated the distribution of glutamic acid decarboxylase 67, a GABA synthetase, which in turn modulated the activity of IL and its downstream brain regions. Collectively, our findings elucidate the molecular modifier of IL inhibitory neurons in regulating memory specificity and anxiety, and provide candidates for developing therapeutic strategies for the prevention or treatment of a series of fear generalization-related neuropsychiatric disorders.

保持适当水平的恐惧记忆特异性对于个体的生存和心理健康至关重要，而过度泛化的恐惧通常发生在神经精神疾病中，包括创伤后应激障碍和广泛性焦虑症。然而，调节恐惧记忆特异性的分子机制仍然知之甚少。内侧前额叶皮层 (mPFC) 被认为是恐惧记忆调节的关键大脑区域。先前的转录组学研究已经确定，plexin-A1 是一种对轴突发育至关重要的跨膜受体，在恐惧记忆训练后，它在 mPFC 中被下调。在这项研究中，我们发现学习诱导的 plexin-A1 mRNA 和蛋白质水平下调特别发生在 mPFC 边缘下皮层 (IL) 的抑制性而非兴奋性神经元中。通过病毒介导的功能性突变体在 IL 抑制神经元中选择性过度表达对 plexin-A1 的进一步研究揭示了 plexin-A1 在调节记忆特异性和焦虑方面的关键作用。此外，我们的研究结果表明，plexin-A1 调节谷氨酸脱羧酶 67（一种 GABA 合成酶）的分布，进而调节 IL 及其下游脑区的活性。总的来说，我们的研究结果阐明了 IL 抑制性神经元在调节记忆特异性和焦虑方面的分子调节剂，并为开发预防或治疗一系列恐惧泛化相关神经精神疾病的治疗策略提供了候选对象。