BIOL 163 |
| Fragile X syndrome (FXS) is usually caused by transcriptional silencing of the FMR1 gene, which encodes the fragile X mental retardation protein (FMRP). The "mGluR theory" of FXS suggests that key aspects of the syndrome are caused by exaggerated signaling by group 1 metabotropic glutamate receptors (mGluRs). A prediction of the theory is that some rescue could be achieved by down-regulating mGluRs, either pharmacologically or genetically. We have studied the maturation of excitatory synapses in hippocampal cultures prepared from Fmr1 knockout (KO) and wild-type (WT) mice with the aim of testing this prediction. Findings to date indicate that dendrites of neurons lacking FMRP have a significantly higher density of GluR2, synapsin puncta and spines than controls. GluR2 puncta per 10 µm measured 7.0 ± 1.4 in WT (n = 4) and 11.1± 0.8 in KO (n = 7) neurons (P = 0.04). Similarly, synapsin puncta per 10 µm measured 7.2 ± 1.1 in WT (n = 5) and 11.7 ± 0.9 in KO (n = 10) neurons (P = 0.017). We also find that synaptic GluR2 expression is differentially affected by transient activation of mGluRs with DHPG (100 µM) in WT and KO neurons. DHPG treatment produces significant loss of synaptic GluR2 in cultures from KO (43 ± 6 % of untreated controls), but not WT animals (100 ± 20 % of untreated controls). Experiments are currently underway to see if chronic treatment of the cultures with MPEP, an mGluR antagonist, can rescue these phenotypes. Supported by HHMI, NIH, and FRAXA. |
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Chemistry and Metabolism
4:30 PM-6:30 PM, Tuesday, 12 September 2006 Moscone Center -- Hall D, Poster
Division of Biological Chemistry |