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.
Due to the lengthy and expensive drug discovery process (i.e., ~8?15 years and ~800?1,800 million dollars per drug), any effective treatment for intellectual disability seems still many years away. Here, we propose to develop the progenitor-based cell therapy to reverse the learning deficit associated with fragile X, which may lead to quick-to-market or -clinic treatments for the cognitive impairment of patients with fragile X.
