outside-in: rethinking the etiology of autism spectrum ... · medicine and a ph.d. in...
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SCIENCE sciencemag.org 4 OCTOBER 2019 • VOL 366 ISSUE 6461 45
PH
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LA
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EF
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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: [email protected]
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sciencemag.org SCIENCE46 4 OCTOBER 2019 • VOL 366 ISSUE 6461
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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
1. C. J. Cascio, J. Neurodev. Disord. 2, 62 (2010). 2. Diagnostic and Statistical Manual of Mental Disorders:
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,
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14. J. Baio et al., MMWR Surveill. Summ. 67, 1 (2018).
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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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Outside-in: Rethinking the etiology of autism spectrum disordersLauren L. Orefice
DOI: 10.1126/science.aaz3880 (6461), 45-46.366Science
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