Li Heng, Choi Jennifer Ja-Yoon, Huang Eric J, Xu Baoji
Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL, USA.
Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA.
bioRxiv. 2025 Jul 12:2025.07.09.663876. doi: 10.1101/2025.07.09.663876.
Fragile X syndrome (FXS) results from loss of FMR1-encoded FMRP and is associated with reduced density of parvalbumin (PV) neurons; however, the mechanism underlying this abnormality remains unknown. Here we report that microglial FMRP regulates PV neuron density through lysosomal function. Mice with deletion in microglia exhibited audiogenic seizures (AGS) and decreased PV neuron density in the cortex and AGS-associated inferior colliculus (IC). FMRP increased the expression of lysosomal genes in microglia, including the progranulin-encoding gene. Its loss in microglia led to impaired lysosomal function and increased apoptosis in microglia and PV neurons. Furthermore, PV neuron density in the IC was reduced similarly in male , , and ; mice, and AAV8-mediated overexpression of progranulin rescued AGS and PV neuron loss in mice. This indicates that progranulin insufficiency is a determinant for PV neuron loss in FXS and elevating progranulin is a therapeutic strategy for FXS.
脆性X综合征（FXS）是由FMR1编码的FMRP缺失引起的，与小白蛋白（PV）神经元密度降低有关；然而，这种异常背后的机制仍然未知。在此，我们报告小胶质细胞FMRP通过溶酶体功能调节PV神经元密度。小胶质细胞缺失的小鼠表现出听源性癫痫发作（AGS），并且皮质和与AGS相关的下丘（IC）中的PV神经元密度降低。FMRP增加了小胶质细胞中溶酶体基因的表达，包括编码颗粒蛋白前体的基因。其在小胶质细胞中的缺失导致溶酶体功能受损，以及小胶质细胞和PV神经元中细胞凋亡增加。此外，IC中的PV神经元密度在雄性Fmr1 KO、Fmr1 KO/Grn KO和Grn KO小鼠中同样降低，并且腺相关病毒8（AAV8）介导的颗粒蛋白前体过表达挽救了Fmr1 KO小鼠中的AGS和PV神经元损失。这表明颗粒蛋白前体不足是FXS中PV神经元损失的一个决定因素，而提高颗粒蛋白前体水平是FXS的一种治疗策略。
