While researchers have long known the genetic defect underlying FragileX syndrome, they are still tracing how that defect creates the complexmix of mental retardation, hyperactive behavior, attention deficits,and other problems in the disorder. Fragile X is particularly importantbecause it is the most common single-gene cause of mentalretardation--affecting about 1 in 4000 males and 1 in 8000 females inthe U.S.
In an article in the August 4, 2005, issue of Neuron,researchers led by Chris De Zeeuw of Erasmus University Rotterdamreport that they have pinpointed a specific cause of defects in motorlearning in Fragile X patients. Their work represents the firstinvestigation of the role of abnormalities in the brain's cerebellum inFragile X syndrome.
Fragile X syndrome is caused by a defect in the Fragile Xmental retardation 1 (Fmr1) gene, which in turns produces anonfunctioning protein, FMRP. In their studies, De Zeeuw and colleaguesstudied the behavioral effects on motor learning and the effects onneurons in the cerebellum of knocking out this gene.
They found that mice lacking the gene showed deficits in aparticular motor learning task known to be largely controlled by thecerebellum. In this "eyeblink conditioning" task, the mice were taughtto associate a stimulus such as a tone with a puff of air on their eye,and the blink response was measured as an indication of how well theanimals could learn the task. The researchers found that micecompletely lacking the Fmr1 gene showed deficits in the motor learningtask. But most importantly, the researchers also found that micelacking the Fmr1 gene only in specific neurons, called Purkinje cells,in the cerebellum showed the deficit.
Detailed electrophysiological studies of Purkinje cells in suchmutant mice revealed that the cells showed an enhanced weakening oftheir signaling connections--called long-term depression. Theresearchers also found that the Purkinje cells showed abnormalities instructures called dendrites, which are the branches from nerve cellsthat contain the receiving stations for signals from other neurons.
When the researchers conducted similar eyeblink conditioning tests in Fragile X patients, they found the same severe deficits.
And when the researchers created a mathematical model oflong-term depression, they found that they could link alteration insignaling between neurons in the cerebellum with impairment in motorlearning processes.
"Thus, while a lack of FMRP in areas such as the cerebralcortex, amygdala, and hippocampus may induce cognitive symptoms inFragile X syndrome, the current data allow us to conclude that a lackof functional FMRP in cerebellar P cells may equally well lead todeficits in motor learning in Fragile X patients," concluded theresearchers.
The researchers include S.K.E. Koekkoek, B.A. Milojkovic, B.R.Dortland, T.J.H. Ruigrok, W. De Graaf, A.E. Smit, F. VanderWerf, C.E.Bakker, R. Willemsen, E. Mientjes, M. Joosten, B.A. Oostra, and C.I. DeZeeuw of Erasmus MC, Rotterdam, The Netherlands; K. Yamaguchi,T. Ikeda,S. Kakizawa, K. Onodera, and M. Ito of RIKEN, Saitama, Japan; R. Maexand E. De Schutter of University of Antwerp, Belgium; and D.L. Nelsonof Baylor College of Medicine, Houston, Texas. This work was supportedby the Dutch Organization for Medical Sciences, Life Sciences,Neuro-Bsik consortium, and the European Community (EC). B.A.O.,S.K.E.K., and D.L.N. were supported by NIH and FRAXA ResearchFoundation. E.D.S. and R.M were supported by EC and IUAP and FWO(Belgium).
Koekkoek et al.: "Deletion of FMR1 in Purkinje Cells EnhancesParallel Fiber LTD, Enlarges Spines, and Attenuates Cerebellar EyelidConditioning in Fragile X Syndrome." Publishing in Neuron, Vol. 47,pages 339--352, August 4, 2005. DOI 10.1016/j.neuron.2005.07.005 www.neuron.org
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