Orefice LL, Zimmerman AL, Chirila AM, Sleboda SJ, Head JP,
Ginty DD.
Peripheral Mechanosensory Neuron Dysfunction Underlies
Tactile and Behavioral
Deficits in Mouse Models of ASDs. Cell. 2016 Jun 8. pii:
S0092-8674(16)30584-0.
doi: 10.1016/j.cell.2016.05.033. [Epub ahead of print]
Abstract
Patients with autism spectrum disorders (ASDs) commonly
experience aberrant tactile sensitivity, yet the neural alterations underlying
somatosensory dysfunction and the extent to which tactile deficits contribute
to ASD characteristics are unknown. We report that mice harboring mutations in
Mecp2, Gabrb3, Shank3, and Fmr1 genes associated with ASDs in humans exhibit
altered tactile discrimination and hypersensitivity to gentle touch. Deletion
of Mecp2 or Gabrb3 in peripheral somatosensory neurons causes mechanosensory
dysfunction through loss of GABAA receptor-mediated presynaptic inhibition of
inputs to the CNS. Remarkably, tactile defects resulting from Mecp2 or Gabrb3
deletion in somatosensory neurons during development, but not in adulthood,
cause social interaction deficits and anxiety-like behavior. Restoring Mecp2
expression exclusively in the somatosensory neurons of Mecp2-null mice rescues
tactile sensitivity, anxiety-like behavior, and social interaction deficits, but
not lethality, memory, or motor deficits. Thus, mechanosensory processing
defects contribute to anxiety-like behavior and social interaction deficits in
ASD mouse models.
____________________________________________________________________
Autism spectrum disorders (ASDs) are characterized by
impaired social interactions and repetitive behaviors, often accompanied by
abnormal reactions to sensory stimuli.
ASD is generally thought to be caused by deficits in brain
development, but a study in mice, published June 9 in Cell, now suggests that
at least some aspects of the disorder, including the perception of touch and
the presence of anxiety and social abnormalities, are linked to defects in
another area of the nervous system—the peripheral nerves found throughout the
limbs, digits and other parts of the body that communicate sensory information
to the brain.
Although we know about several genes associated with ASD, a challenge, and a major goal, has been to find where in the nervous system the problems occur,” Ginty said. “By engineering mice that have these mutations only in their peripheral sensory neurons, which detect light touch stimuli acting on the skin, we’ve shown that mutations there are both necessary and sufficient for creating mice with an abnormal hypersensitivity to touch.”…
Although we know about several genes associated with ASD, a challenge, and a major goal, has been to find where in the nervous system the problems occur,” Ginty said. “By engineering mice that have these mutations only in their peripheral sensory neurons, which detect light touch stimuli acting on the skin, we’ve shown that mutations there are both necessary and sufficient for creating mice with an abnormal hypersensitivity to touch.”…
The investigators measured how the mice reacted to touch
stimuli, such as a light puff of air on their backs, and tested whether they
could discriminate between objects with different textures. Mice with ASD gene
mutations in only their sensory neurons exhibited heightened sensitivity to
touch stimuli and were unable to discriminate between textures.
The transmission of neural impulses between the
touch-sensitive neurons in the skin and the spinal cord neurons that relay
touch signals to the brain was also abnormal. Together, these results show that
mice with ASD-associated gene mutations have deficits in tactile perception…
The investigators next examined anxiety and social
interactions in the mice using established tests and looking at how much mice
avoided being out in the open and how much they interacted with mice they’d
never seen before. Surprisingly, the animals with ASD gene mutations only in
peripheral sensory neurons showed heightened anxiety and interacted less with
other mice.
“How closely these behaviors mimic anxiety seen in ASD in
humans is up for debate,” Ginty said, “but in our field, these are
well-established measures of what we consider to be anxiety-like behavior and
social interaction deficits.”
“A key aspect of this work is that we’ve shown that a
tactile, somatosensory dysfunction contributes to behavioral deficits;
something that hasn’t been seen before,” Ginty said. “In this case, that
deficit is anxiety and problems with social interactions.”
How problems with processing the sense of touch lead to
anxiety and social problems isn’t clear at this point, however…
“Based on our findings, we think mice with these
ASD-associated gene mutations have a major defect in the ‘volume switch’ in
their peripheral sensory neurons,” said first author Lauren Orefice, a
postdoctoral fellow in Ginty’s lab. Essentially, she said, the volume is turned
up all the way in these neurons, leading the animals to feel touch at an
exaggerated, heightened level.
“We think it works the same way in humans with ASD,” Ginty
added.
“The sense of touch is important for mediating our
interactions with the environment, and for how we navigate the world around
us,” Orefice said. “An abnormal sense of touch is only one aspect of ASD, and
while we don’t claim this explains all the pathologies seen in people, defects
in touch processing may help to explain some of the behaviors observed in
patients with ASD.”
Courtesy of Doximity
No comments:
Post a Comment