Insights into activity-dependent neuronal growth through RSRF-supported research

October 20, 2006

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 regulatory loop in which BDNF feeds back to trigger phosphorylation of MeCP2, suggesting that BDNF and neuronal activity may cooperate in regulating MeCP2 function. Finally, this study shows that MeCP2 phosphorylation at S421 occurs only in the brain and not in other tissues. Disruption of this specific phosphorylation mechanism could explain why RTT primarily affects brain function, despite the fact that cells throughout the body express MeCP2. The authors also may have found an explanation for the sleep disturbances that are a frequent complication of RTT: one of the brain regions in which they observed activity-dependent phosphorylation of MeCP2 at S421 is involved in regulating circadian rhythms, including the sleep-wake cycle.

New work by Wang et al. (Katz lab) published in the Journal of Neuroscience examines another aspect of how mutations in MeCP2 disrupt BDNF signaling, namely, the relationship between how much BDNF a neuron expresses and how much is released. Normally, synaptic maturation and function are regulated by precise coupling of activity dependent BDNF expression and secretion. This balance is disrupted in MeCP2-deficient neurons, however, by two factors. On the one hand, mutant neurons exhibit a progressive decline in BDNF content after birth; the timing of this decline varies among different brain regions. On the other hand, mutant neurons release a greater percentage of their BDNF content. Thus, early in development, MeCP2 deficient neurons release more BDNF than normal cells. Such hypersecretion of BDNF in newborn MeCP2-deficient neurons may disturb the delicate, tightly regulated developmental processes elicited by changes in experience-dependent neuronal activity. Eventually, BDNF content declines so much that mutant cells release less BDNF than normal, which is likely to result in synaptic dysfunction. The authors further found that secretory defects are not restricted to neurons that release BDNF. Release of adrenal hormones called catecholamines, which play a key role in the body's response to stress, is also abnormally high in MeCP2- deficient cells. Wang et al. hypothesize that secretory defects could be a common thread contributing to dysfunction of multiple neural systems in RTT.

Source: Rett Syndrome Research Foundation

Explore further: Small-molecule therapeutic boosts spatial memory and motor function in Rett syndrome mice

Related Stories

Small-molecule therapeutic boosts spatial memory and motor function in Rett syndrome mice

July 5, 2017
New research into Rett syndrome therapeutics suggests that a small molecule already reported to improve respiratory problems associated with the disease may also improve spatial memory and motor skill defects.

Rett syndrome drug shows promise in clinical trial

June 23, 2014
Rett syndrome, a rare genetic disorder that causes mental retardation, autism, and physical deformities, has no cure. However, a small clinical trial has found that a growth factor known as IGF1 can help treat some symptoms ...

Rett syndrome gene dysfunction redefined

October 3, 2013
Whitehead Institute researchers have redefined the function of a gene whose mutation causes Rett syndrome, a neurodevelopmental autism spectrum disorder. This new research offers an improved understanding of the defects found ...

Decoding Rett syndrome: New pieces to the puzzle

June 17, 2013
(Medical Xpress)—Rett Syndrome is a neurological disorder that affects about 1 in 10,000 girls. Back in 1992, University of Edinburgh researcher Adrian Bird discovered that the protein, MeCP2, plays a major role in the ...

Recommended for you

Hibernating ground squirrels provide clues to new stroke treatments

November 17, 2017
In the fight against brain damage caused by stroke, researchers have turned to an unlikely source of inspiration: hibernating ground squirrels.

Age and gut bacteria contribute to multiple sclerosis disease progression

November 17, 2017
Researchers at Rutgers Robert Wood Johnson Medical School published a study suggesting that gut bacteria at young age can contribute to multiple sclerosis (MS) disease onset and progression.

Molecular guardian defends cells, organs against excess cholesterol

November 16, 2017
A team of researchers at the Harvard T. H. Chan School of Public Health has illuminated a critical player in cholesterol metabolism that acts as a molecular guardian in cells to help maintain cholesterol levels within a safe, ...

Prototype ear plug sensor could improve monitoring of vital signs

November 16, 2017
Scientists have developed a sensor that fits in the ear, with the aim of monitoring the heart, brain and lungs functions for health and fitness.

Ancient enzyme could boost power of liquid biopsies to detect and profile cancers

November 16, 2017
Scientists are developing a set of medical tests called liquid biopsies that can rapidly detect the presence of cancers, infectious diseases and other conditions from only a small blood sample. Researchers at The University ...

FDA to crack down on risky stem cell offerings

November 16, 2017
U.S. health authorities announced plans Thursday to crack down on doctors pushing stem cell procedures that pose the gravest risks to patients amid an effort to police a burgeoning medical field that previously has received ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.