Turning on a gene later in life can restore typical behavior in mice.
In a study of mice, MIT researchers have now shown that they can
reverse some of those behavioral symptoms by turning the gene back on
later in life, allowing the brain to properly rewire itself.
“This suggests that even in the adult brain we have profound
plasticity to some degree,” says Guoping Feng, an MIT professor of brain
and cognitive sciences. “There is more and more evidence showing that
some of the defects are indeed reversible, giving hope that we can
develop treatment for autistic patients in the future.”
Feng, who is the James W. and Patricia Poitras Professor of
Neuroscience and a member of MIT’s McGovern Institute for Brain Research
and the Stanley Center for Psychiatric Research at the Broad Institute,
is the senior author of the study, which appears in the Feb. 17 issue
of Nature. The paper’s lead authors are former MIT graduate
student Yuan Mei and former Broad Institute visiting graduate student
Patricia Monteiro, now at the University of Coimbra in Portugal.
The Shank3 protein is found in synapses — the connections that allow
neurons to communicate with each other. As a scaffold protein, Shank3
helps to organize the hundreds of other proteins that are necessary to
coordinate a neuron’s response to incoming signals.
Studying rare cases of defective Shank3 can help scientists gain
insight into the neurobiological mechanisms of autism. Missing or
defective Shank3 leads to synaptic disruptions that can produce
autism-like symptoms in mice, including compulsive behavior, avoidance
of social interaction, and anxiety, Feng has previously found.
He has also shown that some synapses in these mice, especially in a
part of the brain called the striatum, have a greatly reduced density of
dendritic spines — small buds on neurons’ surfaces that help with the
transmission of synaptic signals.
In the new study, Feng and colleagues genetically engineered mice so
that their Shank3 gene was turned off during embryonic development but
could be turned back on by adding tamoxifen to the mice’s diet.
When the researchers turned on Shank3 in young adult mice (two to
four and a half months after birth), they were able to eliminate the
mice’s repetitive behavior and their tendency to avoid social
interaction. At the cellular level, the team found that the density of
dendritic spines dramatically increased in the striatum of treated mice,
demonstrating the structural plasticity in the adult brain.
However, the mice’s anxiety and some motor coordination symptoms did
not disappear. Feng suspects that these behaviors probably rely on
circuits that were irreversibly formed during early development.
When the researchers turned on Shank3 earlier in life, only 20 days
after birth, the mice’s anxiety and motor coordination did improve. The
researchers are now working on defining the critical periods for the
formation of these circuits, which could help them determine the best
time to try to intervene.
“Some circuits are more plastic than others,” Feng says. “Once we
understand which circuits control each behavior and understand what
exactly changed at the structural level, we can study what leads to
these permanent defects, and how we can prevent them from happening.”
Gordon Fishell, a professor of neuroscience at New York University
School of Medicine, praises the study’s “elegant approach” and says it
represents a major advance in understanding the circuitry and cellular
physiology that underlie autism. “The combination of behavior, circuits,
physiology, and genetics is state-of-the art,” says Fishell, who was
not involved in the research. "Moreover, Dr. Feng's demonstration that
restoration of Shank3 function reverses autism symptoms in adult mice
suggests that gene therapy may ultimately prove an effective therapy for
Read the whole story at MIT News