Grant: Project Grant

The specific causes of autism and mental retardation are often unknown, but one known cause is a mutation in the fragile X gene (FMR1), which is called Fragile X syndrome (FXS). Knocking-out this gene in mice (Fmr1 KO) provides an animal model with which to study the brain, molecular pathways, and potential treatments for FXS. Neurons often communicate with each other by releasing neurotransmitter molecules at synapses, the small gap between neurons. The receiving end of the synapse typically has the shape of a mushroom, called a dendritic spine, which is found in great numbers on the tree-like array of dendrites of each neuron. There are excess spines in FXS, autism, and Fmr1 KO mice, that are probably due to deficits in the normal spine pruning process that occurs throughout normal childhood development. Microglia are specialized cells that remove dendric spines, and this grant project will examine a particular set of molecules that regulate microglial pruning. We have discovered that two proteins, called eukaryotic translation elongation factor 1-alpha (EF1alpha) and murine double minute2 (mdm2), bind together to form a complex Mdm2-EF1alpha. This Mdm2-EF1alpha complex is abnormally elevated in FXS patients and Fmr1 KO mice. We created a peptide that can block this interaction, thereby reducing the amount of Mdm2-EF1alpha complex and correcting the autism-like behaviors seen in Fmr1 KO mice. In this grant we propose further experiments with this peptide to determine the details of the molecular signaling pathways regulating microglial pruning of spines, and to optimize the delivery of this peptide as a potential new treatment for FXS. Our research will increase knowledge of molecular and cellular disease mechanisms in FXS and identify a potential novel treatment that could correct deficient spine pruning during development. This would be a great advance in medical care, because currently there are no treatments targeting the underlying cause of FXS.