Editorial: Shankopathies: Shank Protein Deficiency-Induced Synaptic Diseases

Elodie Ey, Thomas Bourgeron, Tobias M. Boeckers, Eunjoon Kim, Kihoon Han

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Elodie Ey, Thomas Bourgeron, Tobias M. Boeckers, Eunjoon Kim, Kihoon Han. Editorial: Shankopathies: Shank Protein Deficiency-Induced Synaptic Diseases. Frontiers in Molecular Neuroscience, 2020, 13, pp.11. 10.3389/fnmol.2020.00011. pasteur-03325407

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# Editorial: Shankopathies: Shank Protein Deficiency-Induced Synaptic Diseases

Elodie Ey<fnref n="1" />*, Thomas Bourgeron<fnref n="1" />*, Tobias M. Boeckers²*, Eunjoon Kim³,⁴* and Kihoon Han⁵*

**Keywords:** Shank, Shankopathies, neuropsychiatric disorders, modulating factors, brain regions

## Editorial on the Research Topic

### Shankopathies: Shank Protein Deficiency-Induced Synaptic Diseases

SHANK (also known as ProSAP) proteins are postsynaptic core scaffolds involved in excitatory synapse development, function, and plasticity. The three members of the SHANK family (SHANK1, SHANK2, and SHANK3) differ in their temporal and regional expression patterns in the central nervous system and non-neuronal tissue during development. Mutations in the cognate genes are associated with various neuropsychiatric conditions, such as autism spectrum disorders, Phelan-McDermid syndrome, intellectual disability, schizophrenia, and bipolar disorder. Exactly how defects in SHANK proteins contribute to these conditions is currently under active investigation.

The present Research Topic provides an overview of current knowledge on the involvement of SHANK genes in neuropsychiatric disorders. Shankopathies are explored at different scales: genes, proteins, cells, synapses, neural circuits, behaviors, and environment. For example, Eltokhi et al. observed that the large phenotypic diversity of patients carrying SHANK2 mutations is reflected in the phenotypic diversity displayed by the various *Shank2* mouse models. Hassani Nia and Kreienkamp reviewed the effects of *Shank3* mutations on the gene, protein, and synaptic signaling. Both reviews provide a comprehensive state-of-the-art overview on SHANK2 and SHANK3 different scales. An example of how mouse models can closely mimic human Shankopathies was provided by the comprehensive characterization of the *Shank3*Q321R knock-in model conducted by Yoo et al..

The other contributions address two major questions for Shankopathies: (i) Are there specific modulating factors for Shankopathies and (ii) Which brain regions are specifically affected by Shankopathies?

Concerning the first question, three putative modulating factors were examined; namely, pharmacological intervention (pharmacological modulation of phenotypes), sexual hormones, and zinc. Sungur et al. explored whether *Shank1* mutant mice and control mice were equally sensitive to amphetamine and methylenedioxymethamphetamine. In *Shank2* mutant mice, Ey et al. demonstrated that the abnormal social behavior of *Shank2* knockout mice was associated with a deficit in social motivation, but with an intact social recognition phenotype. They also highlighted that methylphenidate is ineffective in restoring typical activity levels in hyperactive *Shank2* knockout mice. By contrast, Berkel et al. examined the role of an inherent modulating factor; namely, sexual hormones, on *Shank1*, *Shank2*, and *Shank3* gene transcription and protein

**OPEN ACCESS**

Edited and reviewed by:
Robert J. Harvey,
University of the Sunshine
Coast, Australia

*Correspondence:
Elodie Ey
elodie.ey@pasteur.fr
Thomas Bourgeron
thomas.bourgeron@pasteur.fr
Tobias M. Boeckers
Tobias.Boeckers@dzne.de
Eunjoon Kim
kime@kaist.ac.kr
Kihoon Han
neurohan@korea.ac.kr

Received: 06 December 2019
Accepted: 14 January 2020
Published: 07 February 2020

**Citation:** Ey E, Bourgeron T, Boeckers TM, Kim E and Han K (2020) Editorial: Shankopathies: Shank Protein Deficiency-Induced Synaptic Diseases. *Front. Mol. Neurosci.* 13:11. doi: 10.3389/fnmol.2020.00011

<footnote n="1">¹Human Genetics and Cognitive Functions, Institut Pasteur, UMR 3571 CNRS, Université de Paris, Paris, France, ²Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany, ³Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea, ⁴Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea, ⁵Department of Neuroscience, and Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea</footnote>
levels. The role of sexual hormones as transcriptional fine-
tuners, especially shortly before or after birth, might explain
sex-related differences in patients and animal models. Finally,
zinc was identified as a potentially major modulating factor in
Shankopathies, given its role in recruiting Shank2 and Shank3
at synapses, as well as having a key role in the gastro-intestinal
tract, as reviewed by Hagmeyer et al.. At the molecular level,
the mode of regulation of AMPA receptor (AMPAR) subunit
composition by Shank2, Shank3 and zinc was explored by Ha
et al.. Zinc regulated the switch during development of AMPARs
lacking GluA2 to AMPARs containing GluA2, while Shank2 and
Shank3 also regulated this process. At the scale of the organism,
Fourie et al. tested the effect of long-term zinc supplementation in
alimentation of the *Shank3*<sup>Δex13-16</sup> mouse model. Importantly,
some aspects of synaptic transmission and some behavioral
traits, such as self-grooming, were rescued. Taken together,
the studies on zinc presented in this Research Topic present
evidence that zinc is a promising potential new therapeutic agent
for Shankopathies.

Regarding the second question on brain regions specifically
affected by Shankopathies, different approaches were used to
investigate the effect of *Shank* mutations at the different scales
of observation. Yoo *et al.* highlighted that a conditional *Shank3*
knockout (targeting exons 14–16, encoding the PDZ domain)
in GABAergic neurons (enriched in the striatum) induces
a strong reduction of excitatory synaptic inputs onto dorsal
striatal neurons as observed in global *Shank3*<sup>Δex14–16</sup>
mutant mice. However, the conditional knockout leads to milder social
deficits and stereotyped behaviors than global *Shank3*<sup>Δex14–16</sup>
mutant mice. Using magnetic resonance imaging (MRI), Schoen
et al. examined mouse brain anatomy during development
showing that total brain volume, cerebellar volume, and cortical
thickness were unaffected in homozygous and heterozygous
*Shank3* mutant mice and the prenatal zinc deficiency model
compared to wild-type controls. By contrast, the striatal volume
and the globus pallidus volume were increased in both models,
while the changes in the thalamus were reduced in the *Shank3*
mouse model and increased in the prenatal zinc deficiency mouse
model. Transcriptomic analyses allowed (Jin *et al.*) to identify
brain region-specific modulation of gene expression in different
*Shank3* models, across age classes and between brain regions
(prefrontal cortex, striatum, and hippocampus). This analysis
highlighted an important modulation of the expression of
myelin-related and ribosome-related genes. At the protein level,
Heise *et al.* found that *Shank2* and *Shank3* mutant mice displayed
a reduced expression of receptors specific to excitatory synaptic
transmission in the striatum and in the thalamus (for *Shank2*
also in the cortex and cerebellum). These models were compared
to another mouse model of neurodevelopmental disorders, the
*Cntn4* mutant that displays increased surface expression of

glutamatergic receptors (GluA1 and GluA2) in the striatum or
downregulation of GABAergic receptors (GABAA) in several
brain regions. Finally, the involvement of the reward system was
examined directly and indirectly. In the direct approach, Bariselli
et al. knocked down *Shank3* in the ventral tegmental area in
mice and observed a dysfunction in social-seeking behavior. The
indirect approach concerned the characterization of a *Shank2*
model in another species, namely the *Shank2*Δ<sup>ex31</sup> mutant rat,
characterized by Modi *et al.*. *Shank2*Δ<sup>ex31</sup> mutant rats displayed
an atypically high motivation to collect food reward, in parallel
with social deficits, impaired learning, increased activity, and
repetitive circling, combined with increased striatal activity and
decreased hippocampal function.

In summary, this Research Topic provided a multi-scale
overview of the current state of knowledge on Shankopathies.
The research studies contribute to the understanding of the
spectrum of disorders related to *SHANK* mutations, as well
as providing prospects for new potential therapeutic strategies,
targeting specific brain regions or modulating factors.

AUTHOR CONTRIBUTIONS

All authors listed have made a substantial, direct and intellectual
contribution to the work, and approved it for publication.

FUNDING

This work was supported by the Centre National de la Recherche
Scientifique, the Université de Paris, the Institut Pasteur, and
the Bettencourt-Schueller foundation (to EE and TB), by
the Deutsche Forschungsgemeinschaft (DFG, German Research
Foundation)-Projektnummer 251293561-SFB 1149 (project A2)
(to TMB), by the Institute for Basic Science (IBS-R002-
D1 to EK), and by the National Research Foundation of Korea
(2018R1C1B6001235 to KH). TMB was further supported by
the BIU2 initiative, the Else Kröner Foundation, the Innovative
Medicines Initiative (IMI) Joint Undertaking under grant
agreement no. 777394 (AIMS 2 Trials), which is composed of
financial contributions from the European Union and EFPIA
companies' in-kind contribution and the DZNE, Ulm site.

**Conflict of Interest:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2020 Ey, Bourgeron, Boeckers, Kim and Han. This is an open-access
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