Kang Muwon, Kim Seoyeong, Shin Wangyong, Kim Kyungdeok, Jung Yewon, Choi Woochul, Paik Se-Bum, Kim Eunjoon
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 34141, Korea.
Sci Adv. 2025 Sep 19;11(38):eadr7691. doi: 10.1126/sciadv.adr7691. Epub 2025 Sep 17.
Individuals with autism spectrum disorders (ASD) frequently show long-lasting traumatic fear memory, but the underlying mechanisms remain unclear. Here, we report that -mutant mice carrying a human ASD-risk mutation ( mice) show normal acquisition of contextual fear memory but suppressed fear memory extinction and enhanced remote fear memory responses, along with anxiety- and social-related abnormalities. After footshock and fear extinction, these mutants chronically develop occluded neuronal activation in the basal amygdala (BA) detectable at remote fear memory retrieval, which involves suppressed spontaneous excitatory synaptic transmission and neuronal excitability. Chemogenetic activation of mutant BA neurons during fear extinction improves fear memory extinction and remote fear memory responses without affecting anxiety- or social-related phenotypes. This rescue involves normalized spontaneous excitatory synaptic transmission and neuronal excitability. These results suggest that mice, through impaired fear memory extinction, chronically develop suppressed spontaneous excitatory synaptic transmission and neuronal excitability in BA neurons that enhances remote fear memory responses.
患有自闭症谱系障碍（ASD）的个体经常表现出持久的创伤性恐惧记忆，但其潜在机制仍不清楚。在此，我们报告携带人类ASD风险突变的突变小鼠（小鼠）表现出正常的情境恐惧记忆获得，但恐惧记忆消退受到抑制，远程恐惧记忆反应增强，同时伴有焦虑和社交相关异常。在足底电击和恐惧消退后，这些突变体在远程恐惧记忆检索时，基底杏仁核（BA）中长期出现神经元激活受阻，这涉及到自发兴奋性突触传递和神经元兴奋性的抑制。在恐惧消退过程中对突变体BA神经元进行化学遗传学激活可改善恐惧记忆消退和远程恐惧记忆反应，而不影响焦虑或社交相关表型。这种挽救涉及到自发兴奋性突触传递和神经元兴奋性的正常化。这些结果表明，小鼠通过恐惧记忆消退受损，在BA神经元中长期发展出自发兴奋性突触传递和神经元兴奋性的抑制，从而增强远程恐惧记忆反应。
