There is currently no effective treatment for fragile X syndrome-the most common hereditary form of mental retardation. This may soon change, however, according to US scientists. In a recently published study, Kimberly Huber (University of Texas Southwestern Medical School, Dallas, TX, USA) and colleagues from the Howard Hughes Medical Institute, USA, found electrophysiological evidence of altered synaptic plasticity in a mouse model of fragile X syndrome. This finding may lead to the development of an effective treatment for this perplexing disorder.

Fragile X syndrome is caused by a “premutation” on the long arm of the X chromosome, preventing the synthesis of fragile X mental retardation protein (FMRP). In humans, the lack of FMRP leads to varying degrees of mental retardation, as well as learning disability, attention deficit, and hyperactivity.

To identify the underlying mechanism, Huber's team compared synaptic activity in response to electrical stimulation in the hippo-campus of mutant mice lacking FMRP with that in wild-type mice (Proc Natl Acad Sci USA 2002; 99: 7746–50). The researchers found that the mutant mice exhibited enhanced long-term depression (LTD)-a process thought to be involved in memory formation.

“Our findings suggest a new hypothesis for some of the neurological and psychiatric aspects of fragile X syndrome”, says senior researcher Mark Bear (Brown University, Providence, RI, USA). Although he admits that “much more preclinical research is required to test the hypothesis”, Bear is optimistic that “if it holds up, there is the opportunity for developing drugs to treat fragile X and possibly other forms of mental retardation”.

The main reason behind such optimism is that the lack of FMRP causes enhanced metabotropic glutamate receptor (mGluR)-mediated LTD in the hippocampus, without causing any other apparent changes. Therefore, the researchers hypothesise that the learning problems and other symptoms manifested by patients with fragile X are caused by mGluR overactivity, which could be counteracted by the administration of mGluR antagonists.

But other experts are more sceptical. Wickliffe Abraham (University of Otago, Dunedin, New Zealand) cautions, “altered fragile X protein function is expected to have many effects on cell physiology, in addition to altered LTD”. Abraham points out that there is already some published evidence of reduced long-term potentiation (another kind of synaptic plasticity) in the cortex of transgenic mice that lack FMRP (Mole Cell Neurosci 2002; 19: 138–51). He also wonders “whether specifically targeting the enhanced LTD for therapeutic treatment will have any real behavioural benefit, especially since the suggested therapeutic target (mGluR) has more roles to play than just the induction of LTD”.

Nevertheless, Abraham says that the data of Huber and co-workers set the scene for a major assault on the issue. “Since only a specific type of LTD is altered, with a known pharmacology, it is possible that this finding is one step toward finding a useful therapeutic intervention”, he concludes.