Brain needs perfection in synapse number

October 3, 2007

Like Goldilocks, the brain seeks proportions that are just right. The proper number of synapses or communication between nerve cells, determined early in life, is crucial to having a healthy brain that can learn and retain information.

Now, researchers at Baylor College of Medicine in Houston have determined that the protein MeCP2 (methyl-CpG binding protein 2), is critical to fine-tuning the number of synapses. In a report that appears in today’s issue of the journal Neuron, they said that too little MeCP2, as in the neurodevelopmental disorder Rett syndrome, or too much MeCP2, can result in mental retardation, problems with gait or spasticity and symptoms of autism.

In fact, a common underlying theme in the autism spectrum disorders could be a disruption in neuron-to-neuron communication caused by abnormal amounts of MeCP2, said Hsiao-Tuan Chao, an M.D./Ph.D. graduate student, who worked under the co-mentorship of BCM investigators Drs. Huda Y. Zoghbi and Christian Rosenmund and is first author of the report. Zoghbi is a professor of molecular and human genetics, pediatrics, neurology and neuroscience at BCM and a Howard Hughes Medical Institute investigator, and Rosenmund is an associate professor of molecular and human genetics and neuroscience.

As infants, girls with Rett syndrome seem normal for at least six months. Between the ages of 6 and 18 months, however, their development stops and they begin to regress, losing the ability to talk. Then they begin to have problems walking and keeping their balance and develop typical hand-wringing behavior. Many of their symptoms mirror those of autism. Zoghbi’s laboratory was the first to identify a mutation in the MeCP2 gene that results in too little of this protein, causing girls to develop Rett. Boys who suffer from a disorder linked to too much MeCP2 have spasticity and mental retardation with autism-like behavior.

“MeCP2 has an important role in fine-tuning the amount of synaptic responses,” said Chao. Having just the right amount of MeCP2 and the right number of synapses drives healthy brain development.

“Starting life with the right amount of synapses is critical,” said Zoghbi. “What determines that and how do we know that we have the right number?”

Chao unraveled that mystery using two different sets of mice – one with too little MeCP2 and one with too much – and asking what was wrong with their neurons.

“We wanted to know if there were changes within the neuron itself or is this a question of the overall network and the way the neurons communicate?” she said.

In Rosenmund’s laboratory, she was able to use his assays to look at synaptic communication in individual neurons to find out that loss of MeCP2 caused the neurons to “talk on a lower level, releasing less neurotransmitter per neuron,” she said. On the contrary, doubling MeCP2 caused the opposite, an increase in communication between neurons or synapses. Most importantly, she found that synapses were functioning normally, but that too little MeCP2 meant that fewer synapses were formed, while too much MeCP2 meant too many synapses were formed.

“The beauty of this result is that this critical process in the development of synaptic connectivity in the brain is tightly regulated by the amount of MeCP2,” said Rosenmund. “It is one of the strongest pieces of evidence that mental retardation and autism-like diseases originate with problems in synapse formation.”

Chao said, “It suggests that the pathways in which MeCP2 is involved and the proteins it regulates are probably critical for how the brain can determine how many synapses to make as it’s developing.”

“This determination of how many synapses to make happens early in life,” said Zoghbi. “If it’s not right, then the brain undergoes secondary changes to try to compensate. This is a big important observation and opens up ways to think about adult diseases that involve loss of synaptic function. It is also interesting that patients who lack this protein or have too much have features of autism. More and more, data point to the possiblity that autism is a disorder of abnormal function of the synapse.”

“This is important because this is the basic foundation for how we refine our learning,” Chao said. “Understanding how MeCP2 is involved in our neurological development is another piece of the puzzle in understanding autism and other neurological disorders.”

Source: Baylor College of Medicine

Explore further: Why does brain development diverge from normal in autism spectrum disorders?

Related Stories

Why does brain development diverge from normal in autism spectrum disorders?

April 13, 2011
Rett syndrome, a neurodevelopmental disorder on the autism spectrum, is marked by relatively normal development in infancy followed by a loss of loss of cognitive, social and language skills starting at 12 to 18 months of ...

Gene regulation in brain may explain repetitive behaviors in Rett syndrome patients

September 26, 2016
Three-year-old Naomi slaps her forehead a few times, bites her fingers and toddles across the doctor's office in her white and pink pajamas before turning her head into a door with a dull thud. Her mother quickly straps on ...

In what ways does lead damage the brain?

February 29, 2012
Exposure to lead wreaks havoc in the brain, with consequences that include lower IQ and reduced potential for learning. But the precise mechanism by which lead alters nerve cells in the brain has largely remained unknown.

In mouse model of Rett syndrome, research reveals how adult learning is impaired in females

January 18, 2017
Neurodevelopmental disorders like autism very likely have their origin at the dawn of life, with the emergence of inappropriate connectivity between nerve cells in the brain. In one such disorder, Rett syndrome, the pathology ...

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 ...

Recommended for you

Scientists find key to regenerating blood vessels

November 23, 2017
A new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) identifies a signaling pathway that is essential for angiogenesis, the growth of new blood vessels from pre-existing vessels. The ...

Researchers find infectious prions in Creutzfeldt-Jakob disease patient skin

November 22, 2017
Creutzfeldt-Jakob disease (CJD)—the human equivalent of mad cow disease—is caused by rogue, misfolded protein aggregates termed prions, which are infectious and cause fatal damages in the patient's brain. CJD patients ...

Surprising roles for muscle in tissue regeneration, study finds

November 22, 2017
A team of researchers at Whitehead has illuminated an important role for different subtypes of muscle cells in orchestrating the process of tissue regeneration. In a paper published in the November 22 issue of Nature, they ...

Study reveals new mechanisms of cell death in neurodegenerative disorders

November 22, 2017
Researchers at King's College London have discovered new mechanisms of cell death, which may be involved in debilitating neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

How rogue immune cells cross the blood-brain barrier to cause multiple sclerosis

November 21, 2017
Drug designers working on therapeutics against multiple sclerosis should focus on blocking two distinct ways rogue immune cells attack healthy neurons, according to a new study in the journal Cell Reports.

New simple test could help cystic fibrosis patients find best treatment

November 21, 2017
Several cutting-edge treatments have become available in recent years to correct the debilitating chronic lung congestion associated with cystic fibrosis. While the new drugs are life-changing for some patients, they do not ...

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.