Brain-derived neurotrophic factor (BDNF) has been a subject of keen interest in neuroscientific circles for several years, turning up in studies of conditions ranging from central hypoventilation syndrome to obsessive-compulsive disorder, depression, bipolar disorder and schizophrenia -- a range of disorders uncannily parallel to those produced by mutations in the "Rett gene," MeCP2. In 2003, two groups found that MeCP2 regulates BDNF transcription, but sorting out the complex relationship between the two proteins has been quite challenging. New studies from the labs of Michael Greenberg at Children's Hospital Boston and David Katz at Case Western School of Medicine have begun to shed light on the interplay of MeCP2 and BDNF.

Because Rett syndrome (RTT) develops during early childhood, when sensory experiences normally stimulate the development of synaptic circuits, some researchers hypothesized that the fundamental defect in RTT is a failure of synaptic plasticity or maturation. Early support for this hypothesis came from studies showing that MeCP2 expression normally increases as neurons mature. Conversely, RTT patients and mice lacking MeCP2 suffer defects in synaptic plasticity, learning and memory, all of which are dependent on experience so there is some link between experience and the change in neuronal function it would normally produce that is missing when MeCP2 is not functioning properly.

Zhou et al. (Greenberg lab) have found at least part of that missing link. In a paper just published in Neuron, they show that increases in neuronal activity result in phosphorylation of MeCP2 at a particular residue (S421) which, in turn, increases transcription of certain genes, including Bdnf, that are required for experience-dependent brain maturation. They further show that phosphorylation of MeCP2 at S421 is required for structural modifications of neurons that underlie the maturational process. Moreover, they identified a complex regulato
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Contact: Monica Coenraads
monica@rsrf.org
203-243-5733
Rett Syndrome Research Foundation
20-Oct-2006