In the August 4, 2005, issue of Neuron, Ben Oostra and Chris De Zeeuw and colleagues at Erasmus University Rotterdam reported that they pinpointed a specific cause of defects in motor learning in Fragile X patients. Their work is the first investigation of the role of abnormalities in the brain’s cerebellum in Fragile X.

This study evaluated the behavioral effects of the Fragile X mutation on motor learning in both the knockout mice and human patients.

They found that mice lacking the FMR1 gene showed deficits in a motor learning task known to be largely controlled by the cerebellum. In this “eyeblink conditioning” task, the mice were taught to associate a tone with a puff of air on their eye, and the blink response was measured as an indication of how well the animals could learn the task. The researchers found that mice completely lacking the FMR1 gene showed deficits in this motor learning task. But most importantly, the researchers also found that mice lacking the FMR1 gene only in specific neurons, Purkinje cells, in the cerebellum also showed the deficit.

Detailed electrophysiological studies of Purkinje cells in such mutant mice revealed that the cells showed an enhanced weakening of their signaling connections — called long-term depression (LTD). When the researchers conducted similar eyeblink tests in Fragile X patients, they found the same severe deficits.

Results of this work were published in 2008, showing that absence of FMRP affects cerebellar motor learning: Savings and extinction of conditioned eyeblink responses in fragile X syndrome.