Newly
discovered details might advance efforts to reverse Rett syndrome, a rare
condition that prevents an infant’s brain circuitry from developing, according
to a presentation called out as a “Hot Topic” by the Society for Neuroscience
at its annual
meeting this week.
The study
by researchers at the University of Alabama at Birmingham is part of mounting evidence that conditions from autism to
Down syndrome need not last a lifetime.
“Our
results suggest that the field is on the right track in early efforts to design
a treatment for a devastating condition in Rett syndrome,” said Lucas Pozzo-Miller, Ph.D.,
professor of neurobiology at UAB and senior author of the paper. “They also
provide the latest argument that correcting for the genetic miscues behind
developmental disabilities may one day reverse their effect, even if treated in
adulthood.”
Past
studies found that mutations or changes in a single gene, MECP2, are
present in 95 percent of children with Rett syndrome, called RTT, which affects
one in 15,000 children. Located on the X sex chromosome, the mutated gene has
different effects in boys and girls. Boys suffer severe malformation and rarely
survive. Girls appear normal for a few months after birth, but then their motor
skills and cognitive ability regress and they may have seizures.
Previous
work in Pozzo-Miller’s lab established that the nerve cells in RTT children
have fewer dendritic spines, structures that branch from nerve cells to better
pick up signals in the gaps, or synapses, between them. The spines can be
counted as a measure of the ability of nerve cells in the hippocampus, which
directs learning and memory, to relay and store information as circumstances
change.
The work
proceeds from the revolutionary idea that experience changes the physical
wiring of nerve cells. Cells become more closely wired to neighbors in the
nerve pathways most often used, but dwindle when idled. Evidence also suggests
that developing brains build the capacity to think and remember by changing
connection strength between neurons, with the change reflected in dendritic
spine density.
To
understand the role of MECP2 malfunction in reducing the number of
dendritic spines, the team analyzed its density in mice engineered to lack the MECP2
gene.
They
found, as expected, that mutant mice too young to have symptoms yet had a lower
dendritic spine density in hippocampal neurons than their normal counterparts.
Unexpectedly
though, the team also found that when mice lacking MECP2 grew old enough
to become symptomatic, the mice had about the same number of spines on their
dendrites as wild type mice. The finding seemed to call into question the
validity of dendritic spine density as a measure for lost plasticity-related
function in Rett syndrome.
A closer
look, however, revealed that dendritic spines in symptomatic mutant mice, while
as numerous as those in control mice, were “frozen.” They no longer
changed in size, number or shape over time depending on how much the nerve
pathway was stimulated by known triggers like the neurotransmitter glutamate.
“Perhaps
the system tries to compensate for the lack of MECP2 function by
increasing the number of spines formed through abnormal channels,” Pozzo-Miller
said. “This dense, frozen wiring might explain why children with RTT lose
cognitive ability and why they have seizures as sensitive but faulty nerve
connections overload. Further study will tell.”
The paper, titled “Hippocampal CA1 pyramidal
neurons show impaired dendritic spine density and morphology only in
presymptomatic Mecp2 mutant mice,” was presented Monday, Nov. 14, at the
2011 annual meeting of the Society for Neuroscience in Washington, D.C.
Also making an important contribution was Gaston Calfa, Ph.D., a post-doctoral
fellow within UAB Department of Neurobiology. The work was funded by National Institute of
Neurological Disorders and Stroke and the International Rett
Syndrome Foundation.
“The
result further validates dendritic spine density as a useful measure for the
loss of plasticity in developmental disability, and potentially, of the ability
of experimental treatments to restore it,” said Christopher Chapleau, Ph.D., a
post-doctoral fellow in UAB’s Department of Neurobiology and first author on
the paper. “Having a good model is particularly important right now because the
field has identified a protein, BDNF, which drives dendritic spines to grow,
and that might reverse the loss seen in Rett syndrome."
