Description) Although patients affected by fragile X syndrome are in many respects healthy and able to function in normal life, they show mental impairment and dendritic branching anomalies which suggest decreased synaptic plasticity. The investigator has developed a test for determining rapid neurotransmitter-responsive protein synthesis initiation at synapses, which is impaired in mice with a nonfunctional FMRP gene. It is also known that there are dramatically lowered levels of mGluR1, the glutamate receptor responsible for triggering rapid synaptic protein synthesis, in protein extracts from the brain cortex area of these mice, as compared to hippocampus and cerebellum. The investigator speculates that perhaps FMRP is necessary for neurotransmitter-triggered rapid translation of a specific subset of proteins near the synapse, and that some of the receptor proteins may be members of this subset. If the balance of receptors at a synapse is not the normal one, then the response of the synapse may be subtly altered due to disturbed translation regulation. In addition, if the normal developmental sequence is disturbed, then pruning and maturation would likely be affected. This application is designed to test the hypothesis that some neurotransmitter receptors are among the subset of proteins whose postsynaptic synthesis is partially dependent on the presence of FMRP. Both mGluR1 and other receptors will be screened at various developmental ages and in different areas of the brain. Transcription levels, transport, and local translation will be tested. The investigators will question whether the primary deficit, the lack of rapid postsynaptic translation, is due to the lack of receptors or whether, if the system is artificially stimulated, rapid translation can still not proceed due to lack of FMRP. Verification of down-regulation of a particular group of receptors would have dramatic implications for possible avenues of therapy, as it might be possible to trigger some of these receptors by alternative biochemical routes.
| Kim, Soong Ho; Dong, Willie K; Weiler, Ivan Jeanne et al. (2006) Fragile X mental retardation protein shifts between polyribosomes and stress granules after neuronal injury by arsenite stress or in vivo hippocampal electrode insertion. J Neurosci 26:2413-8 |
| Miyashiro, Kevin Y; Beckel-Mitchener, Andrea; Purk, T Patrick et al. (2003) RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 37:417-31 |
| Churchill, James D; Grossman, Aaron W; Irwin, Scott A et al. (2002) A converging-methods approach to fragile X syndrome. Dev Psychobiol 40:323-38 |
