Interneuron-based cell therapy for Fragile X

 描述(申请人提供)：脆性X综合征是最常见的遗传性智力障碍形式，由Fmr1基因编码的脆性X智力低下蛋白(FMRP)功能丧失引起。脆性X患者患有认知障碍，这种障碍在要求注意力的学习中尤为明显。NMDA敏感的谷氨酸受体依赖的长时程增强的损害是由于小GTPase RAS信号介导的突触GluA1在锥体神经元的选择性损害，被认为是Fmr1KO小鼠注意依赖性学习障碍的原因。然而，FMRP功能丧失是如何导致RAS信号通路受损的，目前尚不清楚。最近的研究表明，在Fmr1KO小鼠中，表达小白蛋白和生长抑素的中间神经元介导的神经元间回路发生了改变。这种异常的抑制可能是脆性X综合征动物模型锥体神经元中RAS信号异常的原因。来源于胚胎内侧和尾侧神经节隆起的GABA能前体细胞(MGE和CGE)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来源的祖细胞移植到Fmr1KO小鼠的海马区。我们发现，移植增强了Fmr1 KO小鼠锥体神经元的突触可塑性并挽救了学习障碍，提出了一种有趣的可能性，即MGE和CGE前体可能通过修复受损的神经元间回路、RAS信号和突触可塑性来修复Fmr1 KO小鼠的学习障碍。在这里，我建议探索改善Fmr1 KO小鼠学习能力的细胞疗法(目标1)，并研究细胞疗法如何改善Fmr1 KO小鼠的学习能力(目标2)。这个项目的发现应该会为治疗脆性X患者提供替代的快速临床细胞治疗方案。

 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.