Duke: Sensory problems are common
to autism spectrum disorders. Some individuals with autism may injure
themselves repetitively -- for example, pulling their hair or banging
their heads -- because they’re less sensitive to pain than other people. New research points to a potential mechanism
underlying pain insensitivity in autism. The study, conducted by two
teams at Duke University and appearing online Dec. 1 in the journal
Neuron, is the first to connect autism to one of the most well-studied
pain molecules, called TRPV1 (transient receptor potential ion channel
subtype V1), which is a receptor for the main spicy component of chili
peppers.
“Not enough research has been done on the
mechanisms driving sensory problems in autism, but it’s important
because sensory processing probably affects to some degree how the brain
develops,” said co-author Yong-hui Jiang, M.D., Ph.D., associate
professor of pediatrics and neurobiology at Duke. Jiang collaborated
with Ru-Rong Ji, Ph.D., professor of anesthesiology and neurobiology and
chief of pain research in Duke University School of Medicine’s
Department of Anesthesiology.
In a study published earlier this year, Jiang and other collaborators at Duke described a mouse model of autism
in which they deleted a prominent autism gene called SHANK3, which is
mutated in 1 percent of people with the disorder. These mice show
several features of autism, including social deficits and excessive
self-grooming.
That study did not examine pain. But about 70
percent of individuals with autism or a related disorder called
Phelan-McDermid syndrome who have mutations in SHANK3 are known to have
sensory processing problems, according to Jiang, who treats children
with autism at Duke’s Children Hospital & Health Center.
In the new study, Ji’s group put
SHANK3-deficient mice through a battery of sensory tests, finding that
the animals had lower sensitivity than normal mice to heat and
heat-related pain -- akin to the soreness a person feels after a
sunburn.
It turns out that the SHANK3 protein is
normally present not only in the brain, but also in a cluster of
pain-sensing neurons called the dorsal root ganglion in mice. The group
also found SHANK3 in the same types of cells from human donors who did
not have autism.
“This was a big surprise that SHANK3 is
expressed in the peripheral nervous system, but before this study, no
one had ever looked for it outside of the brain,” Ji said.
The scientists found that TRPV1 and SHANK3
are actually present together in sensory neurons of the dorsal root
ganglion, and that they interact. In the mice missing SHANK3, TRPV1
never makes it to the cell surface, where it normally does its job.
Missing even half of normal level of SHANK3 drastically lowers TRPV1’s
ability to transmit pain signals, suggesting that SHANK3 is a crucial
molecule for pain sensation.
SHANK3 is better known for its role in the
brain. It is found in the tiny clefts called synapses where signals are
passed from one neuron to the next. Until now, it was believed to be
present only in the receiving end of the synapse, called the
postsynaptic terminal, where it acts as a scaffold to secure specific
receptors that receive chemical messages.
The new study also shows that SHANK3 is
expressed on the sending sides of the synapse, called presynaptic
terminals. The scientists hope to understand next what the protein might
be doing there.
“That changes our understanding of how these
two components (of the synapse) work together to contribute to
autism-related behavior and will change how we develop effective
treatments,” Jiang said.
TRPV1 blockers are already the focus of
intense research and development, but these compounds come with side
effects. The new study suggests a more specific way to block TRPV1 --
through its interaction with SHANK3 -- in order to avoid these side
effects, Ji said.
Ji and Jiang are both members of the Duke
Institute for Brain Sciences. The study also includes three co-first
authors: Qingjian Han from Ji’s group who discovered SHANK3 in sensory
neurons and pain defects in SHANK3 mutant mice; Yong Ho Kim, an
electrophysiologist in Ji’s group who found diminished TRPV1 function in
SHANK3 mutant mice; and Xiaoming Wang from Jiang’s lab who generated
SHANK3 mutant mice.
This research was supported by the National
Institutes of Health (R01 NS87988, R01 DE17794, R01 DE22743, R01
MH098114, R21 HD077197, and R21 MH1043136) and the Phelan-McDermid
Syndrome Foundation.
CITATION: "SHANK3 Deficiency Impairs Heat
Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons," Qingjian
Han, Yong Ho Kim, Xiaoming Wang, Di Liu, Zhi-Jun Zhang, Alexandra L.
Bey, Mark Lay, Wonseok Chang, Temugin Berta, Yan Zhang, Yong-Hui Jiang,
and Ru-Rong Ji. Neuron, Dec. 21, 2016. DOI: 10.1016/j.neuron.2016.11.007