Rett syndrome mice improve with deep brain stimulation

Parents love to watch their babies grow, learn new things and celebrate their milestones. Unfortunately, the parents of 1/10000 baby girls, which carry a mutation in a gene on their X chromosome, will witness their child reach their walking and talking milestones, only to lose those abilities. People living with Rett syndrome are severely intellectually disabled. It was once thought that the brain degenerated but it does not. Rett syndrome mouse models can be rescued from neurological symptoms, making a treatment seem more within reach.

While we normally think of treatments as drugs that you take, a potential treatment for Rett syndrome is a procedure called deep brain stimulation (DBS). DBS is electrical stimulation of the brain through an inserted electrode and it is not fully understood how it works. This month is Rett syndrome awareness month and fittingly Nature published a paper showing the success of DBS in reversing learning impairment in a mouse model of Rett syndrome. A study by researchers at Baylor College of Medicine provides hope that certain aspects of Rett syndrome intellectual disability may be reversible in people by using DBS in the future. While putting an electrode into the brain sounds invasive, the procedure is actually fairly routine for neurosurgeons and is used to treat people with Parkinson’s disease and movement disorders. So far it has rarely been used on children.

Rett syndrome is most often caused by a mutation in the MECP2 gene. Mice engineered to be mutated in Mecp2, called RTT mice, show intellectual disability and copy some of the other Rett syndrome features such as motor skill and breathing impairments. Researchers inserted electrodes into the brains of RTT mice in the fimbria-fornix, an area of the brain that controls hippocampal activity and is involved in certain forms of memory. This area of the brain was electrically stimulated for one hour a day for 2 weeks followed by behavioural testing. After DBS treatment the ability of RTT mice to remember a fearful context and show ‘freezing’ behaviour improved to the point that it was as good as normal mice. Spatial cognition was also improved in RTT mice that had been treated with DBS as tested by the ability of mice to locate hidden platforms when swimming.

How DBS works is somewhat mysterious and this study adds insight into the mechanism. The researchers measured long-term potentiation, electrical recordings that indicate an increase in strength of synaptic connections between neurons, which is needed for learning. DBS treatment improved long-term potentiation in the hippocampus. The hippocampus of RTT mice also appeared to generate new neurons in response to DBS.

While the results are encouraging, mice and humans are so different that it is hard to predict how a human would respond to this treatment. Many drugs that look promising in animal cognitive tests do not pan out in human clinical trials. While Rett Syndrome is relatively rare, grouped together intellectual disability affects a large proportion of the population at 2-3%. There is hope that in the future DBS treatments might work for various types of intellectual disabilities.  

References:

Hao, S., Tang, B., Wu, Z., Ure, K., Sun, Y., Tao, H., . . . Tang, J. (2015). Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice. Nature, 430-434. (Get paper)

Cobb, S. (2015). Cognitive disorders: Deep brain stimulation for Rett syndrome. Nature, 331-332. (Get paper)

Deep Brain Stimulation – A Potential Therapeutic for Rett Syndrome? Rett syndrome research trust blog (October 2015)

Image: By Andreashorn (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons https://commons.wikimedia.org/wiki/File%3ADeep_brain_stimulation_electrode_placement_reconstruction.png

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