Cerebellum Dysfunction May Contribute to Rett Motor Problems

Impairments in the cerebellum — a brain region responsible for controlling balance and movement coordination — contribute, in part, to motor impairments associated with Rett syndrome, a mouse study has found.

These findings highlight the importance of understanding which brain areas contribute to the onset of specific symptoms associated with different neurological disorders, including Rett syndrome, according to investigators.

The study, “Deleting Mecp2 from the cerebellum rather than its neuronal subtypes causes a delay in motor learning in mice,” was published in the journal eLife and led by scientists at Baylor College of Medicine.

Rett syndrome is chiefly caused by mutations in the MECP2 gene, which provides instructions to make a protein called MeCP2 that is responsible for controlling the activity of other genes.

In mice, the loss of Mecp2 — the mouse equivalent to the human MECP2 gene — has been reported to cause impairments in motor coordination and learning, as well as tremors and lack of mobility, which are also observed in patients.

Similar impairments have also been found in animals where the Mecp2 gene has been specifically deleted in the cortex or basal ganglia. The cortex is the outermost part of the brain that is involved in behavior, memory, and thought process, while the basal ganglia is a region deep within the brain that is responsible for motor coordination.

However, “little is known about the function of Mecp2 in the cerebellum, a brain region critical for motor function,” the scientists wrote.

Here, they found evidence indicating that cerebellar dysfunctions following the loss of Mecp2 contribute, at least in part, to motor impairments associated with Rett.

After confirming the MeCP2 protein was present in neurons located in the cerebellum, the researchers proceeded to delete Mecp2 in all major cell types found in the cerebellum at the same time, or in specific cell types individually.

They found that when they deleted Mecp2 from all cell types at the same time, mice started showing impairments in motor learning that could be overcome with training. Yet, the same motor learning defects were not observed when Mecp2 was eliminated from specific cell types individually.

In subsequent experiments, the scientists monitored the activity of Purkinje cells — a type of inhibitory neuron found in the cerebellum — of mice lacking Mecp2 when they were awake.

The team discovered these neurons had irregular firing rates (activity) that could not be explained by structural defects or by a reduction in the number of synapses — the sites of near contact where nerve cells communicate — which were both found to be normal.

According to the investigators, these findings suggest the deletion of Mecp2 in the cerebellum affects the firing rates of Purkinje cells, without overly impairing their structure and organization.

“These findings demonstrate that the motor deficits present in Rett syndrome arise, in part, from cerebellar dysfunction. For Rett syndrome and other neurodevelopmental disorders, our results highlight the importance of understanding which brain regions contribute to disease phenotypes [symptoms],” the researchers concluded.