Chen Huan, Qiao Dan, Wang Chang, Zhang Bohan, Wang Zhao, Tang Longmei, Wang Yibo, Zhang Ran, Zhang Yizhou, Song Leigang, Zuo Hongchun, Guo Fangzhen, Wang Xia, Li Sha, Cui Huixian
Department of Anatomy, Hebei Medical University, Shijiazhuang, China.
Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China.
Front Cell Neurosci. 2022 Apr 22;16:872347. doi: 10.3389/fncel.2022.872347. eCollection 2022.
Dysregulated synaptic plasticity is a key feature of neurodevelopmental disorders, including autism. This study investigated whether Fragile X mental retardation protein (FMRP), a selective RNA-binding protein that regulates synaptic protein expression by interacting with miRNAs, mediates the effects of androgens that play an important role in regulating the synaptic plasticity in the hippocampus. Experiments using mouse hippocampal neuron HT22 cells demonstrated that dihydrotestosterone (DHT) increased the expression of postsynaptic density protein 95 (PSD95) by inhibiting FMRP expression. Administration of miR-125a inhibitor upregulated the PSD95 expression and significantly increased the DHT-induced upregulation of PSD95. FMRP knockdown in HT22 cells reduced the expression of miR-125a. Moreover, miR-125a inhibitor upregulated the PSD95 expression in the DHT-treated HT22 cells with FMRP knockdown. Subsequently, the effects of androgen-mediated FMRP in regulating neural behaviors and PSD95 expression and dendritic spines density/morphology were investigated using knockout (KO) and wild-type littermate (WT) mice. The castration of WT mice reduced the androgen levels, aggravated anxiety and depression, and impaired learning and memory and sociability of mice. DHT supplementation post-castration reversed the alterations in density and maturity of dendritic spines of hippocampal neurons and behavioral disorders in WT mice; however, it did not reveal such effects in KO mice. Further, immunohistochemical staining and western blotting analyses after knocking down miR-125a revealed similar effects of castration and post-castration DHT supplementation on PSD95 protein expression. These findings clarified that FMRP mediated the effects of DHT through miR-125a in regulating the expression of hippocampal synaptic protein PSD95. This study provides evidence for the neuroprotective mechanism of androgen in PSD95 expression and dendritic spines density/morphology and suggests that treatment interventions with androgen could be helpful for the management of synaptic plasticity disorders.
突触可塑性失调是包括自闭症在内的神经发育障碍的一个关键特征。本研究调查了脆性X智力低下蛋白（FMRP），一种通过与微小RNA相互作用来调节突触蛋白表达的选择性RNA结合蛋白，是否介导了雄激素在调节海马体突触可塑性中所起的重要作用。使用小鼠海马神经元HT22细胞进行的实验表明，二氢睾酮（DHT）通过抑制FMRP表达来增加突触后致密蛋白95（PSD95）的表达。施用miR-125a抑制剂上调了PSD95的表达，并显著增加了DHT诱导的PSD95上调。HT22细胞中FMRP基因敲低降低了miR-125a的表达。此外，miR-125a抑制剂在FMRP基因敲低的DHT处理的HT22细胞中上调了PSD95的表达。随后，使用基因敲除（KO）小鼠和野生型同窝仔鼠（WT）研究了雄激素介导的FMRP在调节神经行为、PSD95表达以及树突棘密度/形态方面的作用。WT小鼠去势降低了雄激素水平，加重了焦虑和抑郁，并损害了小鼠的学习记忆和社交能力。去势后补充DHT逆转了WT小鼠海马神经元树突棘密度和成熟度的改变以及行为障碍；然而，在KO小鼠中未发现此类作用。此外，敲低miR-125a后的免疫组织化学染色和蛋白质印迹分析显示，去势和去势后补充DHT对PSD95蛋白表达有类似影响。这些发现阐明了FMRP通过miR-125a介导DHT在调节海马突触蛋白PSD95表达中的作用。本研究为雄激素在PSD95表达以及树突棘密度/形态方面的神经保护机制提供了证据，并表明雄激素治疗干预可能有助于管理突触可塑性障碍。
