According to new results, fragile X mental retardation protein might have an important role in regulating synaptic plasticity. These findings could be a first step towards identifying potential therapeutic targets in fragile X syndrome.
The protein that is absent in fragile X syndrome, FMRP (fragile X mental retardation protein), might have an important role in regulating synaptic plasticity, according to new results. As well as increasing our understanding of the disorder, the findings could be a first step towards identifying potential therapeutic targets.
Fragile X syndrome is the most common inherited form of mental retardation, and results from a repeat-expansion mutation in the FMR1 gene, which encodes FMRP. Although there is evidence that FMRP binds certain messenger RNAs and regulates their translation into protein, its exact function remains unclear. Huber et al. investigated whether mice with a null mutation in the Fmr1 gene showed any changes in synaptic plasticity that could account for the effects of the human mutation on the brain. Previous work had shown that the protein-synthesis-dependent phase of long-term potentiation in the hippocampus of the knockout mouse was normal, but Huber et al. decided to look at another form of hippocampal plasticity — long-term depression (LTD) — following the demonstration that LTD also requires local protein synthesis. Surprisingly, they found that LTD in the knockout mice was enhanced, so that a train of stimulation produced greater depression of synaptic function than in control mice.
LTD can also be induced by directly stimulating metabotropic glutamate receptors using the agonist DHPG (3,5-dihydroxyphenylglycine). The knockout mice also showed stronger LTD in response to DHPG application than did wild-type mice. However, a different type of LTD that is mediated by NMDA (N-methyl-D-aspartate) receptors rather than by metabotropic glutamate receptors was unaffected.
Although the enhancement of LTD in the knockout mice was unexpected, it is consistent with other work showing that FMRP, which is one of the proteins that is translated following glutamatergic stimulation at a synapse, can negatively regulate the translation of some mRNAs. In the absence of FMRP, other proteins might be excessively translated after stimulation, leading to enhanced LTD.
An intriguing hint as to the connection between FMRP and LTD comes from evidence that one of the proteins whose translation is controlled by FMRP is MAP1b, which regulates synaptic structure and function. Future investigations will no doubt focus on the role of MAP1b in LTD. Although the authors of the paper comment that their data "point to a rational pharmaceutical approach for fragile X syndrome", many questions are raised by this study, and the next instalment will be awaited with interest.
Rachel Jones
References
Huber, K. M. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA99, 7746–7750 (2002) | PubMed |
