Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism spectrum disorder. The mesocorticolimbic system, which includes the prefrontal cortex (PFC), basolateral amygdala (BLA), and nucleus accumbens core (NAcC), is essential for regulating socioemotional behaviors. We employed optogenetics to compare the functional properties of the BLA->NAcC, PFC->NAcC, and reciprocal PFCBLA pathways in Fmr1–/y::Drd1a-tdTomato male mice. In FXS mice, the PFCBLA reciprocal pathway was unaffected, while significant synaptic modifications occurred in the BLA/PFC->NAcC pathways. We observed distinct changes in D1 striatal projection neurons (SPNs) and separate modifications in D2 SPNs. In FXS mice, the BLA/PFC->NAcC-D2 SPN pathways demonstrated heightened synaptic strength. Focusing on the BLA->NAcC pathway, linked to autistic symptoms, we found increased AMPAR and NMDAR currents and elevated spine density in D2 SPNs. Conversely, the amplified firing probability of BLA->NAcC-D1 SPNs was not accompanied by increased synaptic strength, AMPAR and NMDAR currents, or spine density. These pathway-specific alterations resulted in an overall enhancement of excitatory-to-spike coupling, a physiologically relevant index of how efficiently excitatory inputs drive neuronal firing, in both BLA->NAcC-D1 and BLA->NAcC-D2 pathways. Finally, the absence of fragile X messenger ribonucleoprotein 1 (FMRP) led to impaired long-term depression specifically in BLA->D1 SPNs. These distinct alterations in synaptic transmission and plasticity within circuits targeting the NAcC highlight the potential role of postsynaptic mechanisms in selected SPNs in the observed circuit-level changes. This research underscores the heightened vulnerability of the NAcC in the context of FMRP deficiency, emphasizing its pivotal role in the pathophysiology of FXS.

脆性 X 综合征 (FXS) 是智力障碍和自闭症谱系障碍的遗传原因。中皮质边缘系统包括前额皮质 (PFC)、基底外侧杏仁核 (BLA) 和伏核核心 (NAcC)，对于调节社会情绪行为至关重要。我们采用光遗传学来比较Fmr1–/y::Drd1a-tdTomato雄性小鼠中 BLA->NAcC、PFC->NAcC 和互惠 PFCBLA 通路的功能特性。在 FXS 小鼠中，PFCBLA 交互通路不受影响，而 BLA/PFC->NAcC 通路发生显着的突触修饰。我们观察到 D1 纹状体投射神经元 (SPN) 的明显变化和 D2 SPN 的单独修改。在 FXS 小鼠中，BLA/PFC->NAcC-D2 SPN 通路表现出突触强度增强。关注与自闭症症状相关的 BLA->NAcC 通路，我们发现 D2 SPN 中 AMPAR 和 NMDAR 电流增加，棘密度增加。相反，BLA->NAcC-D1 SPN 放电概率的放大并不伴随突触强度、AMPAR 和 NMDAR 电流或棘密度的增加。这些通路特异性改变导致兴奋性与尖峰耦合的整体增强，这是 BLA->NAcC-D1 和 BLA->NAcC-D2 通路中兴奋性输入如何有效驱动神经元放电的生理相关指标。最后，脆弱的 X 信使核糖核蛋白 1 (FMRP) 的缺失导致长期抑郁受损，特别是在 BLA->D1 SPN 中。针对 NAcC 的环路内突触传递和可塑性的这些明显变化凸显了选定 SPN 中突触后机制在观察到的环路水平变化中的潜在作用。 这项研究强调了 FMRP 缺陷背景下 NAcC 的脆弱性，强调其在 FXS 病理生理学中的关键作用。