GENE LINKED TO INCREASED DENTRITIC SPINES :AUTISM FINDINGS
Scientists at the UNC
School of Medicine have discovered that knocking out the gene NrCAM leads to an
increase of dendritic spines on excitatory pyramidal cells in the brains of
mammals. Other studies have confirmed that the overabundance of dendritic
spines on this type of brain cell allows for too many synaptic connections to
form between neurons – a phenomenon strongly linked to autism.
The finding, published
in The Journal of Neuroscience, adds evidence that NrCAM is a major
player in neurological disorders. Previous UNC studies showed that knocking out
the NrCAM gene caused mice to exhibit the same sorts of social behaviors
associated with autism in humans.
“There are many genes
involved in autism, but we’re now finding out exactly which ones and how
they’re involved,” said Patricia Maness, PhD, professor of biochemistry and
biophysics and senior author of the Journal of Neuroscience paper. “Knowing
that NrCAM has this effect on dendrites allows us to test potential drugs, not
only to observe a change in behaviors linked to autism but to see if we can
improve dendritic spine abnormalities, which may underlie autism.
Maness’s finding comes
on the heels of a report from Columbia University researchers who found an
overabundance of the protein MTOR in mice bred to develop a rare form of
autism. By using a drug to limit MTOR in mice, the Columbia researchers were
able to decrease the number of dendritic spines and thus prune the
overabundance of synaptic connections during adolescence. As a result, the
social behaviors associated with autism were decreased. However, the drug used
to limit MTOR can cause serious side effects, and it is located inside cells,
making it a potentially difficult protein to target.
It is too early to
tell if NrCAM and MTOR are linked, but Maness is now studying if the decreased
amount of the NrCAM protein could trigger activation of MTOR. If so, then
NrCAM, which is an accessible membrane-bound protein, might be a preferred
therapeutic target for certain autism-related conditions.
In their study, Maness
and her colleagues found that the NrCAM protein forms a complex with two other
molecules to create a receptor on the membrane of excitatory pyramidal neurons.
Maness’s team found that this receptor allows dendritic spines to retract,
allowing for proper neuron pruning during maturation of the cortex. As a
result, excitatory and inhibitory synapses between neurons develop in a
balanced ratio necessary for brain circuits to function properly.
Maness, a member of
the UNC Neuroscience Center and the Carolina Institute for Developmental
Disabilities, also said that there are likely many other proteins downstream of
NrCAM that depend on the protein to maintain the proper amount of dendritic spines.
Decreasing NrCAM could allow for an increase in the levels of some of these
proteins, thus kick starting the creation of dendritic spines.
“Basic science in
autism is converging in really exciting ways,” Maness said. “Too many spines
and too many excitatory connections that are not pruned between early childhood
and adolescence could be one of the chief problems underlying autism. Our goal
is to understand the molecular mechanisms involved in pruning and find
promising targets for therapeutic agents.”
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