Buffalo: Scientists at the University at Buffalo
have identified the mechanisms behind a genetic mutation that
produces certain autistic behaviors in mice, as well as therapeutic
strategies to restore normal behaviors. The research describes the cellular and molecular basis behind
some autistic behaviors; it also suggests potential biomarkers and
pharmaceutical targets. Published May 28 in Cell Reports, the research
was led by Zhen Yan, PhD, professor in the Department of Physiology
and Biophysics in the UB School of Medicine and Biomedical
Sciences.
The paper focuses on the loss of a gene called Shank3, an
important risk factor for autism spectrum disorders (ASD). The
researchers trace how this risk factor disrupts communication
between neurons, leading to social deficits in mice. And, in their
most important finding, they are able to reverse these neuronal
disruptions, restoring normal behavior in mice.
Previous studies have shown that approximately 84 percent of
people with a Shank3 deletion or loss-of-function mutation had an
ASD. But just how this occurs has remained unknown.
The paper states that mice with a Shank3 deficiency exhibited
“drastically reduced” interest in social stimuli, i.e.,
other mice, versus inanimate objects, suggesting “severe
social deficits.” They also spent significantly more time in
repetitive self-grooming than normal mice.
The UB researchers found that the Shank3 deficiency plays a key
role in how neurons communicate. It has a significant effect on the
activation of the NMDA (n-methyl-D-aspartate) receptor, which is
critical to learning and memory.
Yan explained that the Shank3 deficiency disrupts the
trafficking of this receptor and its function at critical
transmission sites in the brain. That disruption, they found,
results from the dysregulation of actin filaments, which act
as a kind of cellular “highway” in the brain’s
prefrontal cortex, the command center for “high-level”
executive functions and a key region implicated in ASD.
“This research is the first to show that, in animals,
abnormal actin regulation causes autism-like behaviors,” said
Yan.
“Actin filaments are very dynamic structures that
are constantly being assembled and disassembled, processes
controlled by numerous regulators,” Yan explained.
When something upsets the equilibrium of actin filament
assembly, key cellular functions fall apart.
“With Shank3 deficiency, we have found that the
expression or activity of some actin regulators, such as cofilin,
is altered,” explained Yan. “This upsets the
equilibrium of actin filament assembly, which, in turn, disrupts
the normal delivery and maintenance of NMDA and other critical
receptors.”
The result is a very significant effect on the functional
plasticity of the synapse, which, in turn, leads to the
manifestation of some autistic behaviors.
In its most dramatic finding, the researchers found they were
able to reverse this process, restoring normal behaviors in the
Shank3-deficient mice, once the activity of cofilin or other
regulators was returned to normal. This, in turn, restored actin
dynamics at cortical synapses, allowing for the normal trafficking
and functioning of NMDA receptors.
“Once actin filaments and NMDA receptors returned to
normal, we observed a robust and long-lasting rescue of the social
interaction deficits and repetitive behavior in the
Shank3-deficient mice,” said Yan. “Our results suggest
a promising therapeutic strategy for treating autism.”
The researchers are seeking funding to continue their work
developing potential biomarkers and treatments for autism.
- See more at: http://www.buffalo.edu/news/releases/2015/05/045.html#sthash.oSDiUMEC.dpuf