Articles
https://doi.org/10.1038/s41593-018-0110-8
1
Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY,
USA.
2
Center for Computational Research, New York State Center of Excellence in Bioinformatics & Life Sciences, State University of New York at Buffalo,
Buffalo, NY, USA. These authors contributed equally: Luye Qin and Kaijie Ma. *e-mail: zhenyan@buffalo.edu
M
ouse models that reflect the core symptoms of ASD, includ-
ing deficits in sociability and repetitive behaviors, are cru-
cial for preclinical investigations of pathophysiological
mechanisms and novel treatment avenues
1
. Haploinsufficiency of
the SHANK3 gene, which encodes a master scaffolding protein in the
postsynaptic density of glutamatergic synapses
2
, is causally linked
to 22q13.3 deletion syndrome (also known as Phelan–McDermid
syndrome), which conveys a high risk for ASD
3–6
. Deletion or
loss-of-function mutations of one copy of SHANK3 account for
0.5–2.0% of ASD and intellectual disability cases
5,6
. Human genetic
studies of ASD have found that enriched mutations are located at
the SHANK3 C-terminal region (exon 21)
4
, which contains binding
sites for actin (and cortactin) and mGluR (and Homer) and plays a
crucial role in the synaptic targeting and postsynaptic assembly of
Shank3 complex.
Mouse models with Shank3 deficiency exhibit autism-associated
behaviors to different extents
7–16
. Male heterozygous mice with
C-terminal (exon 21) deleted Shank3 (Shank3
+/ΔC
), which exhibit
reduced full-length Shank3 expression
11,12
and loss of synaptic local-
ization of the truncated Shank3 protein
12
, recapitulate social pref-
erence deficits and repetitive behaviors
12
. These behavioral deficits
in Shank3
+/ΔC
mice are attributable to the loss of NMDA-receptor
(NMDAR) function and synaptic trafficking due to actin dysregu
-
lation in pyramidal neurons of prefrontal cortex (PFC)
12
, a brain
region that plays an essential role in mediating social cognition
17
.
Large-scale genetic studies have revealed that many ASD-
associated genes are involved in synaptic homeostasis, transcrip
-
tional regulation and chromatin-remodeling pathways
18–21
. This
prompted us to speculate that targeting epigenetic enzymes to nor
-
malize gene expression and ameliorate synaptic defects may be a
potential strategy to relieve social deficits in ASD. Here we targeted
HDAC family proteins, which generally cause silencing of gene
expression via condensing the chromatin architecture. HDACs play
a key role in cognitive processes
22,23
, and altered histone acetylation
and transcriptional dysfunction have been implicated in psychiatric
disorders
24
; however, the efficacy of HDAC-targeting agents in mod-
els of ASD is unknown. Here we have identified an HDAC inhibitor
that persistently alleviates social deficits in Shank3-deficient mice.
Results
Treatment with the HDAC inhibitor romidepsin lastingly relieves
autism-like social deficits in Shank3-deficient mice. The level of
global H3 acetylation (Fig. 1a) in the frontal cortex of Shank3
+/ΔC
mice was significantly lower than that from wild-type (WT) mice.
A systemic administration of low-dose romidepsin (0.25 mg/kg,
intraperitoneally (i.p.), once daily for 3 d), a highly potent and brain-
permeable class I-specific HDAC inhibitor (with nanomolar in
vitro potency
25
) approved by the US Food and Drug Administration
(FDA) for cancer treatment
26–28
, significantly elevated the level of
acetylated H3 in Shank3
+/ΔC
mice, while it had little effect in WT
mice. These data suggest that Shank3-deficient mice have an abnor
-
mally low level of histone acetylation, which can be restored by
romidepsin treatment.
Next, we examined the impact of romidepsin on social deficits
in young (5–6 weeks old) male Shank3
+/ΔC
mice, which exhibit
loss of social preference in the three-chamber social-interaction
assay
12
. As shown in Fig. 1b,d, during the presentation of both
social (Soc) and nonsocial (NS) stimuli, romidepsin (0.25 mg/kg,
i.p, 3× )-treated Shank3
+/ΔC
mice spent significantly more time
exploring the social stimulus over the nonsocial object, similarly
to WT mice, while saline-injected Shank3
+/ΔC
mice showed a sig-
nificant loss of the preference for the social stimulus. WT mice
treated with romidepsin had unchanged social preferences. The sig
-
nificantly elevated social preference index in Shank3
+/ΔC
mice after
romidepsin treatment (Fig. 1c) suggests that romidepsin alleviates
the observed social deficits.
Social deficits in Shank3-deficient mouse
models of autism are rescued by histone
deacetylase (HDAC) inhibition
Luye Qin
1
, Kaijie Ma
1
, Zi-Jun Wang
1
, Zihua Hu
2
, Emmanuel Matas
1
, Jing Wei
1
and Zhen Yan
1
*
Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes
are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I his-
tone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2
transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits.
Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in
Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin
treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA-receptor
function and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism under-
lying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing
SHANK3 mutations.
Corrected: Publisher Correction
NATURE NEUROSCIENCE | VOL 21 | APRIL 2018 | 564–575 | www.nature.com/natureneuroscience
564
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