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
Reads0
Chats0
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
More filters
Journal ArticleDOI
Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders
Li Zhu,Xiaoming Wang,Xin-lei Li,Aaron J. Towers,Xinyu Cao,Ping Wang,Rachel A. Bowman,Hyuna Yang,Jennifer L. Goldstein,Yi-Ju Li,Yong-hui Jiang +10 more
TL;DR: The ability to alter the epigenetic modification and expression of SHank3 by environmental factors suggests that SHANK3 may be a valuable biomarker for dissecting the role of gene and environment interaction in the etiology of ASD.
Journal ArticleDOI
The Autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations.
Elodie Ey,Elodie Ey,Nicolas Torquet,Nicolas Torquet,Anne-Marie Le Sourd,Anne-Marie Le Sourd,Claire S. Leblond,Claire S. Leblond,Tobias M. Boeckers,Philippe Faure,Thomas Bourgeron +10 more
TL;DR: This study characterised in depth the emission of pup and adult ultrasonic vocalisations of wild-type mice and their ProSAP1/Shank2(-/-) littermates lacking a synaptic scaffold protein mutated in ASD and confirms that ProSap1/ Shank2 (-/-) mice represent a relevant model to study communication defects.
Journal ArticleDOI
Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring.
Alexander Kolevzon,Benjamin Angarita,Lauren Bush,A. Ting Wang,Yitzchak Frank,Amy Yang,Robert Rapaport,Jeffrey M. Saland,Shubhika Srivastava,Cristina Farrell,Lisa Edelmann,Joseph D. Buxbaum +11 more
TL;DR: Recommendations are established to assess the medical, genetic, and neurological features of PMS, which remains a rare disorder and majority of physicians have never seen a case.
Journal ArticleDOI
Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits
Haley E. Speed,Mehreen Kouser,Zhong Xuan,Jeremy M. Reimers,Christine F. Ochoa,Natasha Gupta,Shunan Liu,Craig M. Powell +7 more
TL;DR: This work identifies clear alterations in synaptic function and behavior in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation and lays the foundation for future studies aimed to validate and study region-selective and temporally selective genetic reversal studies in the Shank3G/G mouse that was engineered with such experiments in mind.
Journal ArticleDOI
Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling
Melanie Richter,Nadeem Murtaza,Robin Scharrenberg,Sean H. White,Ole Johanns,Susan Walker,Susan Walker,Ryan K. C. Yuen,Ryan K. C. Yuen,Birgit Schwanke,Bianca Bedürftig,Melad Henis,Melad Henis,Sarah Scharf,Vanessa Kraus,Ronja Dörk,Jakob Hellmann,Zsuzsa Lindenmaier,Jacob Ellegood,Henrike Hartung,Henrike Hartung,Vickie Kwan,Jan Sedlacik,Jens Fiehler,Michaela Schweizer,Jason P. Lerch,Ileana L. Hanganu-Opatz,Fabio Morellini,Stephen W. Scherer,Stephen W. Scherer,Karun K. Singh,Froylan Calderon de Anda +31 more
TL;DR: Evidence is provided that TAOK2 is a neurodevelopmental disorder risk gene and RhoA signaling is identified as a mediator of TAok2-dependent synaptic development and pharmacological enhancement of RHoA activity rescues synaptic phenotypes.
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.
Related Papers (5)
Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.
Christelle M. Durand,Catalina Betancur,Tobias M. Boeckers,Juergen Bockmann,Pauline Chaste,Fabien Fauchereau,Gudrun Nygren,Maria Råstam,I. Carina Gillberg,Henrik Anckarsäter,Eili Sponheim,Hany Goubran-Botros,Richard Delorme,Nadia Chabane,Marie-Christine Mouren-Simeoni,Philippe de Mas,Eric Bieth,Bernadette Rogé,Delphine Héron,Lydie Burglen,Christopher Gillberg,Marion Leboyer,Thomas Bourgeron +22 more