Fragile X (FRAX) syndrome is the most common inherited cause of mental retardation occurring in up to 1 per 1000 males and up to 1 per 2500 females. Due to their significant cognitive and behavioral limitations, affected individuals require care, support, and supervision throughout life and they make up a large segment of the institutionalized population. Recent findings have demonstrated that the FRAX syndrome phenotype is caused by the absence of the fragile X mental retardation protein (FMRP) which is coded by the affected gene. So far, however, little is known about the normal expression of FMRP, so it is uncertain whether its absence is more likely to lead to global brain dysfunction of to dysfunction of particular population of neurons.
Aim 1 will examine this question by characterizing the regional and cellular expression of FMRP in rat and human. Increasing evidence has indicated that FMRP is an RNA binding protein that associates with ribosomes. Based on our preliminary studies, we hypothesize that FMRP is transported into the neuronal nucleus where it selectively binds to a specific complement of mRNAs and then is transported into the neuronal nucleus where it selectively binds to a specific complement of mRNAs and then is transported with them to a subset of cytoplasmic ribosomes, including those present in dendrites and dendritic spines. We further hypothesize that among the mRNA species that associate with FMRP are one or more that are specifically relevant for dendritic function. Thus, the lack of FMRP could compromises synaptic function leading to mental retardation.
Aim 2 will test this model by determining whether FMRP can be localized to each of the predicted subcellular regions. It remains completely unknown how FRAX syndrome affects the brain. The limited neuropathological data from imaging and postmortem brain examinations, have not disclosed any definitive alterations in FRAX syndrome brains. An animal model of FRAX syndrome, the FMRP knockout mouse, has recently been developed that has a phenotype remarkable similar to the human disorder and, as in human, there are no gross brain alterations. Our preliminary studies, however, suggest more subtle alterations in spine and synapse morphology in the hippocampus of the knockout mouse. Since the morphology of dendrites and dendritic spines are very sensitive to synaptic function, we hypothesize that such changes are related to the cognitive deficits that occur in FRAX syndrome.
In aim 3, we will examine comprehensively whether there are any detectable cellular or synaptic changes in the hippocampus of the FMRP knockout mouse.
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