- Record: found
- Abstract: found
- Article: found
Maternal stress in Shank3 ex4-9 mice increases pup-directed care and alters brain white matter in male offspring
research-article
Author(s):
Bibiana K. Y. Wong
1
,
2 ,
Jaclyn B. Murry
3 ,
Rajesh Ramakrishnan
1
,
2 ,
Fang He
1 ,
Alfred Balasa
4 ,
Gary R. Stinnett
5 ,
Steen E. Pedersen
5 ,
Robia G. Pautler
5 ,
Ignatia B. Van den Veyver
1
,
2
,
3
,
*
Publication date (Electronic):
8 November 2019
Journal:
PLoS ONE
Publisher:
Public Library of Science
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Abstract
Gene-environment interactions contribute to the risk for Autism Spectrum Disorder (ASD). Among environmental factors, prenatal exposure to stress may increase the risk for ASD. To examine if there is an interaction between exposure to maternal stress and reduced dosage or loss of Shank3, wild-type (WT), heterozygous (HET) and homozygous (HOM) female mice carrying a deletion of exons four through nine of Shank3 ( Shank3 ex4-9 ) were exposed to chronic unpredictable mild stress (CUMS) from prior to conception throughout gestation. This study examined maternal care of these dams and the white matter microstructure in the brains of their adult male offspring. Overall, our findings suggest that maternal exposure to CUMS increased pup-directed care for dams of all three genotypes. Compared to WT and HET dams, HOM dams also exhibited increased maternal care behaviors with increased time spent in the nest and reduced cage exploration, regardless of exposure to CUMS. Diffusion tensor imaging showed higher mean fractional anisotropy in the hippocampal stratum radiatum of WT and HOM male offspring from dams exposed to CUMS and HOM offspring from unexposed dams, compared to WT male offspring from unexposed dams. These data support that CUMS in Shank3-mutant dams results in subtle maternal care alterations and long-lasting changes in the white matter of the hippocampus of their offspring.
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Most cited references47
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- Abstract: found
- Article: not found
Shank3 mutant mice display autistic-like behaviours and striatal dysfunction
João Peça, Cátia Feliciano, Jonathan T. Ting … (2011)
Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. Shank3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for development of 22q13 deletion syndrome (Phelan-McDermid Syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for Shank3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviours in mice.
- Record: found
- Abstract: found
- Article: found
Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication
Background SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans. Methods We used mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors. Results In Shank3 heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with θ-burst pairing (TBP) or high-frequency stimulation, was impaired in Shank3 heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in Shank3 heterozygous mice. Male Shank3 heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls. Conclusions We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting therapeutic target in Shank3-haploinsufficiency syndromes.
- Record: found
- Abstract: found
- Article: found
Autism risk factors: genes, environment, and gene-environment interactions
Pauline Chaste, Marion Leboyer (2012)
The aim of this review is to summarize the key findings from genetic and epidemiological research, which show that autism is a complex disorder resulting from the combination of genetic and environmental factors. Remarkable advances in the knowledge of genetic causes of autism have resulted from the great efforts made in the field of genetics. The identification of specific alleles contributing to the autism spectrum has supplied important pieces for the autism puzzle. However, many questions remain unanswered, and new questions are raised by recent results. Moreover, given the amount of evidence supporting a significant contribution of environmental factors to autism risk, it is now clear that the search for environmental factors should be reinforced. One aspect of this search that has been neglected so far is the study of interactions between genes and environmental factors.
Author and article information
Contributors
Bibiana K. Y. Wong: Role: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original
draft
Jaclyn B. Murry:
ORCID: http://orcid.org/0000-0002-9879-427X
Role: Formal analysisRole: InvestigationRole: Methodology
Rajesh Ramakrishnan:
ORCID: http://orcid.org/0000-0001-8841-570X
Role: Formal analysisRole: InvestigationRole: Writing – review & editing
Fang He: Role: Formal analysisRole: Investigation
Alfred Balasa: Role: Formal analysisRole: InvestigationRole: Methodology
Gary R. Stinnett: Role: Formal analysisRole: InvestigationRole: Methodology
Steen E. Pedersen: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole:
Visualization
Robia G. Pautler: Role: ConceptualizationRole: InvestigationRole: Methodology
Ignatia B. Van den Veyver:
ORCID: http://orcid.org/0000-0002-0651-5924
Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
Alexandra Kavushansky: Role: Editor
Journal
Journal ID (nlm-ta): PLoS One
Journal ID (iso-abbrev): PLoS ONE
Journal ID (publisher-id): plos
Journal ID (pmc): plosone
Title:
PLoS ONE
Publisher:
Public Library of Science
(San Francisco, CA USA
)
ISSN
(Electronic):
1932-6203
Publication date
(Electronic):
8
November
2019
Publication date Collection: 2019
Volume: 14
Issue: 11
Electronic Location Identifier: e0224876
Affiliations
[1
]
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas,
United States of America
[2
]
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston,
Texas, United States of America
[3
]
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas,
United States of America
[4
]
Department of Pediatrics, Section of Pediatrics Neurology and Developmental Neuroscience,
Baylor College of Medicine, Houston, Texas, United States of America
Author notes
[¤a]
Current address: Noldus Information Technology Inc., Leesburg, Virginia, United States of America
[¤b]
Current address: Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California, United States of America
[¤c]
Current address: Department of Biology, University of St. Thomas, Houston, Texas, United States of America
[¤d]
Current address: The Third Affiliated Hospital of Guangzhou Medical Hospital, Guangzhou, Guangdong, China
[¤e]
Current address: Department of Medical Physics Georgia Institute of Technology, Atlanta, Georgia, United States of America
[¤f]
Current address: Department of Medical Foundations, Ross University School of Medicine, Miramar, Florida, United States of America
* E-mail:
iveyver@
123456bcm.edu
Author information
Jaclyn B. Murry
http://orcid.org/0000-0002-9879-427X
Rajesh Ramakrishnan
http://orcid.org/0000-0001-8841-570X
Ignatia B. Van den Veyver
http://orcid.org/0000-0002-0651-5924
Article
Publisher ID: PONE-D-19-15139DOI: 10.1371/journal.pone.0224876
PMC ID: 6839842
PubMed ID: 31703095
SO-VID: 8829b4f0-c027-49d9-b3ec-ed6fe7fb2907
Copyright © © 2019 Wong et al
License:
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
History
Date
received
: 28
May
2019
Date
accepted
: 23
October
2019
Page count
Figures: 5,
Tables: 0,
Pages: 14
Funding
Funded by: funder-id http://dx.doi.org/10.13039/100007857, Intellectual and Developmental Disabilities Research Center;
Award ID: 1U54HD083092-04
Funded by: funder-id http://dx.doi.org/10.13039/100000097, National Center for Research Resources;
Award ID: C06RR029965
Funded by: funder-id http://dx.doi.org/10.13039/100000861, Burroughs Wellcome Fund;
Award ID: 1008200
Award Recipient
:
ORCID: http://orcid.org/0000-0002-9879-427X
Jaclyn B. Murry
Funded by: funder-id http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
Award ID: T32GM008307
Award Recipient
:
ORCID: http://orcid.org/0000-0002-9879-427X
Jaclyn B. Murry
JBM was supported by a training fellowship from the Burroughs Wellcome Fund (BWF)-The
Houston Laboratory and Population Science Training Program in Gene-Environment Interaction
of the University of Texas Health Science Center at Houston (BWF Grant No.1008200)
and by a T32GM008307 from the National Institute of General Medical Sciences (NIGMS).
The project described was also supported by Grant Number C06RR029965 from the National
Center for Research Resources (NCRR). This work was also supported by the neurobehavioral
core of the Baylor College of Medicine Intellectual and Developmental Disabilities
Research Center (IDDRC) supported by award 1U54HD083092-04 from the Eunice Kennedy
Shriver National Institute for Child Health and Human Development (NICHD). The content
is solely the responsibility of the authors and does not represent the official views
of the BWF and the NIGMS, NCRR and NICHD of the National Institutes of Health. We
note that while BKYW is a current employee of Noldus Information Technology Inc.,
she was not affiliated with Noldus Information Technology Inc. in any shape or form
during the study design, data collection and analysis, decision to publish, or preparation
of the manuscript.
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