Saturday, June 18, 2016

Autism and somatosensory dysfunction

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]

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.”…

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

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