Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3
Xiaoming Wang,Portia A. McCoy,Ramona M. Rodriguiz,Yanzhen Pan,H. Shawn Je,Adam C. Roberts,Caroline J. Kim,Janet Berrios,Jennifer S. Colvin,Danielle Bousquet-Moore,Isabel Lorenzo,Gang Yi Wu,Richard J. Weinberg,Michael D. Ehlers,Michael D. Ehlers,Benjamin D. Philpot,Arthur L. Beaudet,William C. Wetsel,Yong-hui Jiang +18 more
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TLDR
It is concluded that loss of major Shank3 species produces biochemical, cellular and morphological changes, leading to behavioral abnormalities in mice that bear similarities to human ASD patients with SHANK3 mutations.Abstract:
SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density (PSD) of excitatory synapses. Small microdeletions and point mutations in SHANK3 have been identified in a small subgroup of individuals with autism spectrum disorder (ASD) and intellectual disability. SHANK3 also plays a key role in the chromosome 22q13.3 microdeletion syndrome (Phelan-McDermid syndrome), which includes ASD and cognitive dysfunction as major clinical features. To evaluate the role of Shank3 in vivo, we disrupted major isoforms of the gene in mice by deleting exons 4-9. Isoform-specific Shank3(e4-9) homozygous mutant mice display abnormal social behaviors, communication patterns, repetitive behaviors and learning and memory. Shank3(e4-9) male mice display more severe impairments than females in motor coordination. Shank3(e4-9) mice have reduced levels of Homer1b/c, GKAP and GluA1 at the PSD, and show attenuated activity-dependent redistribution of GluA1-containing AMPA receptors. Subtle morphological alterations in dendritic spines are also observed. Although synaptic transmission is normal in CA1 hippocampus, long-term potentiation is deficient in Shank3(e4-9) mice. We conclude that loss of major Shank3 species produces biochemical, cellular and morphological changes, leading to behavioral abnormalities in mice that bear similarities to human ASD patients with SHANK3 mutations.read more
Citations
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Journal ArticleDOI
Autism spectrum disorder traits in Slc9a9 knock-out mice
TL;DR: This study provides strong evidence that lack of Slc9a9 leads to ASD‐like behaviors in mice and provides the field with a new mouse model of ASDs.
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Age-dependent decrease of GAD65/67 mRNAs but normal densities of GABAergic interneurons in the brain regions of Shank3-overexpressing manic mouse model.
TL;DR: Age-dependent decrease of GAD65/67 mRNAs but normal densities of certain GABAergic interneurons in the Shank3 transgenic mice are suggested.
Journal ArticleDOI
Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses
Tanja Baecker,Katharina Mangus,Stefanie Pfaender,Resham Chhabra,Tobias M. Boeckers,Andreas M. Grabrucker +5 more
TL;DR: The results show that increased copper levels indeed interfere with intracellular zinc concentrations and affect synaptic ProSAP/Shank levels, which similarly are altered by manipulation of copper and zinc levels through overexpression and knockdown of COMMD1.
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The Cerebellar Involvement in Autism Spectrum Disorders: From the Social Brain to Mouse Models
TL;DR: This review fulfills the need for an organized, clear, and state-of-the-art perspective on cerebellar involvement in ASD, from its connections to the social brain areas (which are the primary sites of ASD impairments) to the use of monogenic mouse models.
Journal ArticleDOI
Early Restoration of Shank3 Expression in Shank3 Knock-Out Mice Prevents Core ASD-Like Behavioral Phenotypes.
Thomas C. Jaramillo,Zhong Xuan,Jeremy M. Reimers,Christine Ochoa Escamilla,Shunan Liu,Craig M. Powell +5 more
TL;DR: The findings support the idea that the underlying mechanisms involving ASD behaviors in mice deficient in Shank3 are susceptible to early genetic correction of Shank3 mutations, as well as the need for early genetic restoration of wild-type Shank3.
References
More filters
Journal ArticleDOI
Diagnostic and Statistical Manual of Mental Disorders
Vijay A. Mittal,Elaine F. Walker +1 more
TL;DR: An issue concerning the criteria for tic disorders is highlighted, and how this might affect classification of dyskinesias in psychotic spectrum disorders.
Journal ArticleDOI
The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism.
Catherine Lord,Susan Risi,Linda Lambrecht,Edwin H. Cook,Bennett L. Leventhal,Pamela C. DiLavore,Andrew Pickles,Michael Rutter +7 more
TL;DR: Algorithm sensitivities and specificities for autism and PD DNOS relative to nonspectrum disorders were excellent, with moderate differentiation of autism from PDDNOS.
Journal ArticleDOI
Optimized survival of hippocampal neurons in B27-supplemented Neurobasal, a new serum-free medium combination
TL;DR: High survival was achieved with osmolarity lower than found in Dulbecco's Modified Eagle's Medium (DMEM), and by reducing cysteine and glutamine concentrations and by the elimination of toxic ferrnous sulphate found in DME/F12, and Neurobasal is a new medium that incorporates modifications to DMEM.
Journal ArticleDOI
Functional impact of global rare copy number variation in autism spectrum disorders
Dalila Pinto,Alistair T. Pagnamenta,Lambertus Klei,Richard Anney,Daniele Merico,Regina Regan,Judith Conroy,Tiago R. Magalhaes,Tiago R. Magalhaes,Catarina Correia,Catarina Correia,Brett S. Abrahams,Joana Almeida,Elena Bacchelli,Gary D. Bader,Anthony J. Bailey,Gillian Baird,Agatino Battaglia,Tom Berney,Nadia Bolshakova,Sven Bölte,Patrick Bolton,Thomas Bourgeron,Sean Brennan,Jessica Brian,Susan E. Bryson,Andrew R. Carson,Guillermo Casallo,Jillian P. Casey,Brian H.Y. Chung,Lynne E Cochrane,Christina Corsello,Emily L. Crawford,Andrew Crossett,Cheryl Cytrynbaum,Geraldine Dawson,Maretha de Jonge,Richard Delorme,Irene Drmic,Eftichia Duketis,Frederico Duque,Annette Estes,Penny Farrar,Bridget A. Fernandez,Susan E. Folstein,Eric Fombonne,Christine M. Freitag,John Gilbert,Christopher Gillberg,Joseph T. Glessner,Jeremy Goldberg,Andrew Green,Jonathan Green,Stephen J. Guter,Hakon Hakonarson,Elizabeth A. Heron,Matthew Hill,Richard Holt,Jennifer L. Howe,Gillian Hughes,Vanessa Hus,Roberta Igliozzi,Cecilia Kim,Sabine M. Klauck,Alexander Kolevzon,Olena Korvatska,Vlad Kustanovich,Clara Lajonchere,Janine A. Lamb,Magdalena Laskawiec,Marion Leboyer,Ann Le Couteur,Bennett L. Leventhal,Anath C. Lionel,Anath C. Lionel,Xiao-Qing Liu,Catherine Lord,Linda Lotspeich,Sabata C. Lund,Elena Maestrini,William M. Mahoney,Carine Mantoulan,Christian R. Marshall,Helen McConachie,Christopher J. McDougle,Jane McGrath,William M. McMahon,Alison K. Merikangas,Ohsuke Migita,Nancy J. Minshew,Ghazala Mirza,Jeff Munson,Stanley F. Nelson,Carolyn Noakes,Abdul Noor,Gudrun Nygren,Guiomar Oliveira,Katerina Papanikolaou,Jeremy R. Parr,Barbara Parrini,Tara Paton,Andrew Pickles,Marion Pilorge,Joseph Piven,Chris P. Ponting,David J. Posey,Annemarie Poustka,Fritz Poustka,Aparna Prasad,Jiannis Ragoussis,Katy Renshaw,Jessica Rickaby,Wendy Roberts,Kathryn Roeder,Bernadette Rogé,Michael Rutter,Laura J. Bierut,John P. Rice,Jeff Salt,Katherine Sansom,Daisuke Sato,Ricardo Segurado,Ana Filipa Sequeira,Lili Senman,Lili Senman,Naisha Shah,Val C. Sheffield,Latha Soorya,Inês Sousa,Olaf Stein,Nuala Sykes,Vera Stoppioni,Christina Strawbridge,Raffaella Tancredi,Katherine E. Tansey,Bhooma Thiruvahindrapduram,Ann P. Thompson,Susanne Thomson,Ana Tryfon,John Tsiantis,Herman Van Engeland,John B. Vincent,Fred R. Volkmar,Simon Wallace,Kai Wang,Zhouzhi Wang,Thomas H. Wassink,Caleb Webber,Rosanna Weksberg,Kirsty Wing,Kerstin Wittemeyer,Shawn Wood,Jing Wu,Brian L. Yaspan,Danielle Zurawiecki,Lonnie Zwaigenbaum,Joseph D. Buxbaum,Rita M. Cantor,Edwin H. Cook,Hilary Coon,Michael L. Cuccaro,Bernie Devlin,Sean Ennis,Louise Gallagher,Daniel H. Geschwind,Michael Gill,Jonathan L. Haines,Joachim Hallmayer,Judith Miller,Anthony P. Monaco,John I. Nurnberger,Andrew D. Paterson,Margaret A. Pericak-Vance,Gerard D. Schellenberg,Peter Szatmari,Astrid M. Vicente,Veronica J. Vieland,Veronica J. Vieland,Ellen M. Wijsman,Stephen W. Scherer,James S. Sutcliffe,Catalina Betancur +181 more
TL;DR: The genome-wide characteristics of rare (<1% frequency) copy number variation in ASD are analysed using dense genotyping arrays to reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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