INSIGHTS

SCIENCE sciencemag.org 4 OCTOBER 2019 • VOL 366 ISSUE 6461 45

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By Lauren L. Orefice

Autism spectrum disorders (ASDs) are

thought to arise exclusively from ab-

errant brain function. Our research

proposes a surprising revision of

this view. We have discovered that

peripheral sensory neurons—neu-

rons 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 sen-

sory overreactivity, social impairments,

and anxiety-like behaviors. These unex-

pected 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, unex-

plained clinical finding. People with ASD

commonly experience aberrant tactile sen-

sitivity: a seemingly innocuous touch, such

as a gentle breeze or a hug, can be unpleas-

ant 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—somatosen-

sory 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 environ-

mental mouse models of ASD dem-

onstrated 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 syn-

drome model), Fmr1 (fragile X syndrome

model), and Cntnap2, as well as a maternal

immune activation model (5–10).

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 differ-

ent cell types throughout the nervous system

and assessed touch sensitivity. Surprisingly,

loss of Mecp2 in excitatory neurons of the

forebrain produced no major ASD pheno-

types. Instead, genetic mutations in periph-

eral somatosensory neurons (neurons that

receive touch signals at the skin) accounted

for the touch overreactivity ob-

served in Mecp2 mutant mice (3, 4).

We found that the physiologi-

cal deficits that cause tactile over-

reactivity across different ASD

models are distinct. In our studies,

peripheral sensory neurons lack-

ing Mecp2 or Gabrb3 exhibited de-

INS IGHTS

NEUROBIOLOGY

Outside-in: Rethinking the etiology of autism spectrum disordersA role for peripheral sensory neurons in autism pathogenesis

P R I Z E E S SAY

Transverse section of a mouse dorsal root

ganglion (DRG), showing neurons transduced with

a virus expressing the b3 subunit of the GABAA

receptor (green), NF200 expression in large-diameter

DRG neurons (yellow), and Hoechst (blue).

Department of Molecular Biology, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA. Email: orefice@molbio.mgh.harvard.edu

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creased inhibitory signaling via the GABAA

receptor (3), whereas those lacking Shank3

were hyperexcitable as a result of potassium

channel loss (4). Peripheral neuron dysfunc-

tion 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 neu-

rons for touch processing is interesting, but

the general behaviors of the conditional

mutant mice we studied were even more re-

markable. Mice with loss of Mecp2, Gabrb3,

or Shank3 only in peripheral sensory neu-

rons demonstrated profound social impair-

ments and anxiety-like behaviors reminiscent

of those observed in patients (3, 4). Further-

more, selective restoration of gene function

only in peripheral sensory neurons, and not

in the brain, was sufficient to normalize tac-

tile 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 phe-

notypes, 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 im-

pairments in adult mice. But how?

Similar to ASD, anxiety-like behaviors

and social impairments are traditionally at-

tributed to brain circuits. However, decades

of research show that the brain does not de-

velop in isolation. Rather, sensory inputs, in-

cluding light, sound, touch, and many other

environmental signals, guide brain develop-

ment (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 periph-

eral 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 im-

prove 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 in-

creased flow of information from pe-

ripheral sensory neurons to the central

nervous system. We therefore reasoned

that augmenting inhibitory signals via

GABAA receptors at peripheral sensory

neurons might reduce tactile overreactiv-

ity. Acute treatment of adult mice with a

GABAA receptor agonist that does not cross

the blood-brain barrier directly reduced

somatosensory neuron excitability and di-

minished tactile overreactivity in six differ-

ent ASD models (4).

We also saw substantial effects with

chronic administration of this agonist start-

ing early in postnatal life. Mice with germ-

line 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 pro-

found side effects associated with drugs that

act on the central nervous system (15).

Together with a growing body of other

research (3, 4, 16–18), our work highlights

that peripheral sensory neurons have a

major role in ASD and that selective treat-

ment of these neurons has the potential to

improve some developmental and behav-

ioral 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 in-

terplay at the center of ASD. j

REFERENCES AND NOTES

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DSM-5 (American Psychiatric Association, ed. 5, 2013). 3. L. L. Orefice et al., Cell 166, 299 (2016). 4. L. L. Orefice et al., Cell 178, 867 (2019). 5. J. Guy, B. Hendrich, M. Holmes, J. E. Martin, A. Bird,

Nat. Genet. 27, 322 (2001). 6. C. Ferguson et al., BMC Neurosci. 8, 85 (2007). 7. J. Peça et al., Nature 472, 437 (2011). 8. C. M. Spencer, O. Alekseyenko, E. Serysheva, L. A. Yuva-

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(1963).

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Jacobson, Psychol. Med. 24, 203 (1994).

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10.1126/science.aaz3880

INS IGHTS | PRIZE ESSAY

GRAND PRIZE WINNER

Lauren Oref ceLauren Orefice received her B.S. in biology from Boston College and her Ph.D. in neuroscience from George-town University. After her

postdoctoral work at Harvard Medical School, Orefice started as an assistant professor in the Department of Molecular Biology at Massa-chusetts 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 develop-mental disorders.

FINALIST

András SzőnyiAndrás Szőnyi received undergraduate degrees in medicine and a Ph.D. in neu-rosciences from the Semmel-weis University in Budapest,

Hungary. He performed research in the Insti-tute of Experimental Medicine of the Hungar-ian Academy of Sciences. Currently, Szőnyi is a postdoctoral fellow in the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland. He studies the cellular mecha-nisms of learning and memory formation in mice using in vivo imaging and optogenetics.www.sciencemag.org/content/336/6461/46.1

FINALIST

Zvonimir VrseljaZvonimir 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 structur-ally and functionally recovered by developing a perfusion technology.www.sciencemag.org/content/336/6461/46.2

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