α-synuclein mice show signs of PD

Newsdesk Evidence of altered synaptic plasticity found in fragile X syndrome 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 hippocampus 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

THE LANCET Neurology Vol 1 July 2002

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 longterm 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. Thomas S May

␣-synuclein mice show signs of PD US researchers have developed transgenic mice expressing a mutated form of human ␣-synuclein. The mice show severe motor impairment in addition to ␣-synuclein inclusions similar to those seen in Parkinson’s disease (PD), an example of a human ␣-synucleinopathy. “This demonstrates for the first time the detrimental role of ␣-synuclein inclusion formation in the mammalian CNS”, says senior investigator Virginia Lee (University of Pennsylvania School of Medicine, Philadelphia, PA, USA). Lee and co-workers generated mice that express the gene encoding A53T human ␣-synuclein, an alanine to threonine mutation found in at least 12 families with familial PD. The researchers tested motor function of the mice using the rotorod test and examined ␣-synuclein-related pathology by immunostaining, comparing them with mice expressing normal human ␣-synuclein (Neuron 2002; 34: 521–33). Transgenic mice homozygous for the mutant gene appeared normal up to the age of 7 months but by 8 months, they began to develop a motor phenotype characterised by reduced ambulation, lack of grooming, and weight loss. At 9 months, mice were severely

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impaired with partial limb paralysis, resistance to passive movement, hind limb freezing, and tremulous motion in some cases. Immunoelectron microscopy revealed ␣-synuclein inclusions composed of 10–16 nm fibrils in the spinal cord, brainstem, deep cerebellar nuclei, deep cerebral white matter, and in some regions of the thalamus. In addition, the investigators found a correlation between motor impairment and the development of ␣-synuclein pathology. By comparison, mice expressing normal wild-type human ␣-synuclein did not show any signs of this lethal phenotype. The authors state that several other transgenic mouse models expressing wild-type and mutant ␣-synuclein have been described recently, but these models neither revealed the differences between wild-type and mutant ␣-synuclein nor did they fully recapitulate the characteristics of human ␣-synuclein pathology. According to Philipp Kahle (Ludwig Maximilians University, Munich, Germany), the next challenge for genetic mouse models of PD is to functionally connect ␣-synuclein pathology with the selective dopaminergic neuron loss that accounts for parkinsonian symptoms. Rebecca Love

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