Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

Rett syndrome is a progressive brain disorder. Individuals with the condition (who are typically girls) grow normally until they are 6-18 months old and then developmentally regress, with symptoms including anxiety, impaired coordination, seizures and breathing problems. Rett syndrome is caused by mutations in the gene that encodes a protein called MeCP2. Researchers know that MeCP2 is vital for “excitatory” neurons in the brain to communicate with (and activate) their neighbors. Neurons that lack MeCP2 tend to make fewer of the connections across which they communicate – called synapses – with others. Many researchers who study Rett syndrome use male mice that lack the MeCP2 protein. This mouse model mimics the symptoms seen in Rett patients, but at a faster and more severe rate. These studies have shown that restoring normal levels of the protein in neurons prevents the majority of Rett-like symptoms in these mice and reverses the disorder. MeCP2 controls the activity of a number of other genes. These include the gene that produces a protein called Brain-Derived Neurotrophic Factor (BDNF), which helps neurons to grow. Sampathkumar et al. have now studied neurons from mouse models of Rett syndrome to investigate whether BDNF can overcome the defects seen in neurons that lack MeCP2. Viewed under a high-powered microscope, the Rett-like neurons appear smaller than healthy neurons and form fewer synapses. However, increasing the amount of BDNF in the diseased neurons restores normal growth and enables the cells to form more synapses. Girls with Rett syndrome tend to have a mixture of healthy neurons and those that do not produce the right amount of MeCP2. To mimic this, Sampathkumar et al. grew a mixture of normal and Rett-like mouse neurons in a culture dish. The healthy neurons did not help the diseased neurons to form the correct number of synapses. However, increasing the levels of BDNF in the Rett-like neurons enhanced their ability to form synapses, and increased their cell size to match their healthy counterparts. Further work is now required to uncover whether manipulating the gene that encodes BDNF – or other genes that MeCP2 controls the activity of – in the brain can reduce the symptoms and slow the progression of Rett syndrome.