Interneuron-based cell therapy for Fragile X

 描述（由申请人提供）：脆性X综合征是遗传性精神障碍的最常见形式，由基因Fmr 1编码的脆性X精神发育迟滞蛋白（FMRP）功能丧失引起。脆性X患者的认知障碍在需要注意力的学习中尤为明显。NMDA敏感性谷氨酸受体依赖性长时程增强的损害，由于选择性损害的小GT3 Ras信号介导的突触GluA1运输锥体神经元，被认为是负责的缺陷的注意力依赖性学习在Fmr1基因敲除小鼠。然而，FMRP功能的丧失如何导致Ras信号转导受损仍不清楚。 最近的研究表明，由小清蛋白和生长抑素表达的中间神经元介导的神经元间回路在Fmr1基因敲除小鼠中发生了改变。这种失调的抑制可以解释脆性X综合征动物模型锥体神经元中Ras信号的异常。来源于胚胎内侧和尾侧神经节隆起（MGE和CGE）的GABA能祖细胞可以修复有缺陷的神经元间回路。我们最近将野生型供体小鼠的MGE和CGE衍生的祖细胞移植到Fmr1 KO小鼠的海马中。我们发现，移植增强了锥体神经元的突触可塑性，挽救了Fmr1 KO小鼠的学习缺陷，提出了一个有趣的可能性，即MGE和CGE祖细胞可能通过修复有缺陷的神经元间回路，Ras信号传导和突触可塑性来挽救Fmr1 KO小鼠的学习缺陷。在这里，我建议探索改善Fmr1 KO小鼠学习能力的细胞疗法（目的1），并研究细胞疗法如何改善Fmr1 KO小鼠的学习能力（目的2）。该项目的研究结果应该为治疗脆性X患者提供替代的快速临床细胞治疗选择。

 DESCRIPTION (provided by applicant): Fragile X syndrome, the most common form of inherited mental impairment, is caused by the loss of function of the fragile X mental retardation protein (FMRP) encoded by gene Fmr1. Fragile X patients have the cognitive impairment that is particularly pronounced in attention-demanding learning. The impairment of the NMDA-sensitive glutamate receptor-dependent long-term potentiation, due to the selective impairment of small GTPase Ras signaling-mediated synaptic GluA1 trafficking in pyramidal neurons, is believed to be responsible for the deficit of attention-dependent learning in Fmr1 KO mice. However, how loss of function of FMRP leads to the impaired Ras signaling remains unclear. Recent studies showed that the interneuronal circuits mediated by parvalbumin- and somatostatin-expressing interneurons are altered in Fmr1 KO mice. The dysregulated inhibitions could account for the aberrant Ras signaling in pyramidal neurons of this animal model for fragile X syndrome. GABAergic progenitor cells derived from the embryonic medial and caudal ganglionic eminences (MGE and CGE) can repair defective interneuronal circuits. We recently transplanted MGE- and CGE-derived progenitor cells of wild type donor mice into the hippocampi of Fmr1 KO mice. We found that the transplantation enhanced synaptic plasticity in pyramidal neurons and rescued learning defects in Fmr1 KO mice, raising an intriguing possibility that MGE and CGE progenitors may rescue learning defects in Fmr1 KO mice via repairing the defective interneuronal circuits, Ras signaling and synaptic plasticity. Here, I propose to explore the cell therapy that improves learning in Fmr1 KO mice (aim 1) and examine how the cell therapy improves learning in Fmr1 KO mice (aim 2). The findings from this project should suggest alternative quick-to-clinic cell therapeutic options for treating fragile X patients.