Essays on Science and SocietyNeurobiology

Outside-in: Rethinking the etiology of autism spectrum disorders

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Science  04 Oct 2019:
Vol. 366, Issue 6461, pp. 45-46
DOI: 10.1126/science.aaz3880

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Transverse section of a mouse dorsal root ganglion (DRG), showing neurons transduced with a virus expressing the β3 subunit of the GABAA receptor (green), NF200 expression in large-diameter DRG neurons (yellow), and Hoechst (blue).


Autism spectrum disorders (ASDs) are thought to arise exclusively from aberrant brain function. Our research proposes a surprising revision of this view. We have discovered that peripheral sensory neurons—neurons outside the brain—are key sites at which ASD-related gene mutations have a critical impact. Dysfunction of peripheral neurons in mouse models disrupts central nervous system development and causes ASD-related phenotypes, including sensory overreactivity, social impairments, and anxiety-like behaviors. These unexpected findings have led us to propose and demonstrate that peripheral neurons are a tractable and effective therapeutic target to improve some ASD-related behaviors.

Too Much Touch: Tactile Sensitivity in ASD

How did we come to this new perspective? Our launching point was a curious, unexplained clinical finding. People with ASD commonly experience aberrant tactile sensitivity: a seemingly innocuous touch, such as a gentle breeze or a hug, can be unpleasant or even painful (1, 2). In fact, sensory overreactivity is so common that it is now a diagnostic factor for ASD (2).

We therefore sought to determine whether somatosensory circuits were affected in ASD, and whether altered tactile sensitivity might contribute to other ASD traits. Our goal was to focus on tractable symptoms—somatosensory abnormalities—as an entry into these complex, heterogeneous disorders.

Peripheral Sensory Neuron Dysfunction Underlies Tactile Overreactivity

We used genetic mouse models for ASD, combined with behavioral testing, anatomy, and electrophysiology, to define the etiology of aberrant tactile sensitivity in ASD. Using assays to assess sensitivity to light touch, we found that monogenic and environmental mouse models of ASD demonstrated tactile overreactivity (3, 4). The models used included mice with germline mutations in ASD-related genes, including Mecp2 (Rett syndrome model), Gabrb3, Shank3 (Phelan-McDermid syndrome model), Fmr1 (fragile X syndrome model), and Cntnap2, as well as a maternal immune activation model (510).

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Taking advantage of the well-characterized somatosensory circuitry (11), we then sought to determine in which cell types ASD-related genes function for normal tactile reactivity. To do so, we used conditional mouse genetics to selectively delete ASD-related genes in different cell types throughout the nervous system and assessed touch sensitivity. Surprisingly, loss of Mecp2 in excitatory neurons of the forebrain produced no major ASD phenotypes. Instead, genetic mutations in peripheral somatosensory neurons (neurons that receive touch signals at the skin) accounted for the touch overreactivity observed in Mecp2 mutant mice (3, 4).

We found that the physiological deficits that cause tactile overreactivity across different ASD models are distinct. In our studies, peripheral sensory neurons lacking Mecp2 or Gabrb3 exhibited decreased inhibitory signaling via the GABAA receptor (3), whereas those lacking Shank3 were hyperexcitable as a result of potassium channel loss (4). Peripheral neuron dysfunction is thus a common feature of ASD mouse models, although this dysfunction can arise via multiple molecular mechanisms.

Peripheral Sensory Neuron Dysfunction Contributes to Select ASD-Related Behaviors

The importance of peripheral sensory neurons for touch processing is interesting, but the general behaviors of the conditional mutant mice we studied were even more remarkable. Mice with loss of Mecp2, Gabrb3, or Shank3 only in peripheral sensory neurons demonstrated profound social impairments and anxiety-like behaviors reminiscent of those observed in patients (3, 4). Furthermore, selective restoration of gene function only in peripheral sensory neurons, and not in the brain, was sufficient to normalize tactile behaviors, anxiety-like behaviors, and some social behaviors (3, 4).

Of course, peripheral sensory neurons are not the sole locus of dysfunction in ASD. Restoration of sensory neuron function did not improve a number of ASD-related phenotypes, including motor dysfunction, early lethality, respiratory deficits, and memory impairments in Mecp2 mutant mice, nor overgrooming or memory impairments in Shank3 mutants (3, 4). Nonetheless, our findings reveal a key locus of dysfunction underlying tactile overreactivity in distinct ASD models, as well as a role for this tactile overreactivity in the genesis of some aberrant cognitive/social behaviors.

Peripheral Sensory Neuron Dysfunction Alters Brain Development and Function

The loss of ASD-related genes in peripheral sensory neurons is therefore sufficient to cause anxiety-like behaviors and social impairments in adult mice. But how?

Similar to ASD, anxiety-like behaviors and social impairments are traditionally attributed to brain circuits. However, decades of research show that the brain does not develop in isolation. Rather, sensory inputs, including light, sound, touch, and many other environmental signals, guide brain development (12, 13).

We reasoned that if sensory perception is profoundly altered early in development, this may affect one's experience of the world and lead to large changes in behavior. Inspired by experiments conducted by Hubel and Wiesel (13), we found that ASD mutations in peripheral sensory neurons are sufficient to alter developmental and functional properties of specific brain circuits (4).

A Novel Therapeutic Target?

Rates of ASD diagnosis are increasing, with 1 in 59 people in the United States reported to be living with ASD. However, there are no FDA-approved treatments for core ASD symptoms (14). Might it be possible to improve peripheral sensory neuron function and, by ameliorating touch overreactivity, help relieve other related ASD symptoms?

Despite disparate pathophysiological mechanisms, a common signature across ASD mouse models appears to be an increased flow of information from peripheral sensory neurons to the central nervous system. We therefore reasoned that augmenting inhibitory signals via GABAA receptors at peripheral sensory neurons might reduce tactile overreactivity. Acute treatment of adult mice with a GABAA receptor agonist that does not cross the blood-brain barrier directly reduced somatosensory neuron excitability and diminished tactile overreactivity in six different ASD models (4).

We also saw substantial effects with chronic administration of this agonist starting early in postnatal life. Mice with germline mutations in Mecp2 and Shank3 showed major improvements in body condition, brain development, anxiety-like behaviors, and some social impairments (4). Because the administered compound does not cross the blood-brain barrier, it avoids the profound side effects associated with drugs that act on the central nervous system (15).

Together with a growing body of other research (3, 4, 1618), our work highlights that peripheral sensory neurons have a major role in ASD and that selective treatment of these neurons has the potential to improve some developmental and behavioral abnormalities associated with ASD. We are moving toward measuring touch overreactivity in humans with ASD and pursuing modulation of peripheral neuron excitability as a potential clinical therapy.

Our work therefore proposes an exciting revision of ASD etiology and therapeutics, highlighting a genetic-environmental interplay at the center of ASD.

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Lauren Orefice received her B.S. in biology from Boston College and her Ph.D. in neuroscience from Georgetown University. After her postdoctoral work at Harvard Medical School, Orefice started as an assistant professor in the Department of Molecular Biology at Massachusetts General Hospital and the Department of Genetics at Harvard Medical School in 2019. Her lab studies the development and function of somatosensory circuits and the ways in which somatosensation is altered in developmental disorders.

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FINALIST András Szőnyi

András Szőnyi received undergraduate degrees in medicine and a Ph.D. in neurosciences from the Semmelweis University in Budapest, Hungary. He performed research in the Institute of Experimental Medicine of the Hungarian Academy of Sciences. Currently, Szőnyi is a postdoctoral fellow in the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland. He studies the cellular mechanisms of learning and memory formation in mice using in vivo imaging and optogenetics.

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FINALIST Zvonimir Vrselja

Zvonimir Vrselja received his M.D. and Ph.D. from J. J. Strossmayer University in Croatia. He completed his postdoctoral training in the laboratory of Nenad Sestan at Yale School of Medicine, where he continues to work as associate research scientist. His research focuses on understanding how brain cells react to anoxic injury following circulatory arrest, and how such cells can be structurally and functionally recovered by developing a perfusion technology.

References and Notes

  1. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 (American Psychiatric Association, ed. 5, 2013).
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