OBJECTIVE: Research is increasingly linking autism spectrum disorders and other neurodevelopmental disorders to synaptic abnormalities ("synaptopathies"). PSD-95 (postsynaptic density-95, DLG4) orchestrates protein-protein interactions at excitatory synapses and is a major functional bridge interconnecting a neurexinneuroligin-SHANK pathway implicated in autism spectrum disorders. METHOD: The authors characterized behavioral, dendritic, and molecular phenotypic abnormalities relevant to autism spectrum disorders in mice with PSD-95 deletion (Dlg4⁻(/)⁻). The data from mice led to the identification of single-nucleotide polymorphisms (SNPs) in human DLG4 and the examination of associations between these variants and neural signatures of Williams' syndrome in a normal population, using functional and structural neuroimaging. RESULTS: Dlg4⁻(/)⁻ showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses. Dlg4⁻(/)⁻ had subtle dysmorphology of amygdala dendritic spines and altered forebrain expression of various synaptic genes, including Cyln2, which regulates cytoskeletal dynamics and is a candidate gene for Williams' syndrome. A signifi-cant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling, both of which characterize Williams' syndrome. CONCLUSIONS: These findings demonstrate that DLG4 gene disruption in mice produces a complex range of behavioral and molecular abnormalities relevant to autism spectrum disorders and Williams' syndrome. The study provides an initial link between human DLG4 gene variation and key neural endophenotypes of Williams' syndrome and perhaps corticoamygdala regulation of emotional and social processes more generally.
OBJECTIVE: Research is increasingly linking autism spectrum disorders and other neurodevelopmental disorders to synaptic abnormalities ("synaptopathies"). PSD-95 (postsynaptic density-95, DLG4) orchestrates protein-protein interactions at excitatory synapses and is a major functional bridge interconnecting a neurexinneuroligin-SHANK pathway implicated in autism spectrum disorders. METHOD: The authors characterized behavioral, dendritic, and molecular phenotypic abnormalities relevant to autism spectrum disorders in mice with PSD-95 deletion (Dlg4⁻(/)⁻). The data from mice led to the identification of single-nucleotide polymorphisms (SNPs) in humanDLG4 and the examination of associations between these variants and neural signatures of Williams' syndrome in a normal population, using functional and structural neuroimaging. RESULTS:Dlg4⁻(/)⁻ showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses. Dlg4⁻(/)⁻ had subtle dysmorphology of amygdala dendritic spines and altered forebrain expression of various synaptic genes, including Cyln2, which regulates cytoskeletal dynamics and is a candidate gene for Williams' syndrome. A signifi-cant association was observed between variations in two humanDLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling, both of which characterize Williams' syndrome. CONCLUSIONS: These findings demonstrate that DLG4 gene disruption in mice produces a complex range of behavioral and molecular abnormalities relevant to autism spectrum disorders and Williams' syndrome. The study provides an initial link between humanDLG4 gene variation and key neural endophenotypes of Williams' syndrome and perhaps corticoamygdala regulation of emotional and social processes more generally.
Authors: Lukas Pezawas; Andreas Meyer-Lindenberg; Emily M Drabant; Beth A Verchinski; Karen E Munoz; Bhaskar S Kolachana; Michael F Egan; Venkata S Mattay; Ahmad R Hariri; Daniel R Weinberger Journal: Nat Neurosci Date: 2005-05-08 Impact factor: 24.884
Authors: M Migaud; P Charlesworth; M Dempster; L C Webster; A M Watabe; M Makhinson; Y He; M F Ramsay; R G Morris; J H Morrison; T J O'Dell; S G Grant Journal: Nature Date: 1998-12-03 Impact factor: 49.962
Authors: Patrick Tarpey; Josep Parnau; Matthew Blow; Hayley Woffendin; Graham Bignell; Charles Cox; James Cox; Helen Davies; Sarah Edkins; Simon Holden; Angelique Korny; Uma Mallya; Jenny Moon; Sarah O'Meara; Adrian Parker; Philip Stephens; Claire Stevens; Jon Teague; Andrew Donnelly; Marie Mangelsdorf; John Mulley; Michael Partington; Gillian Turner; Roger Stevenson; Charles Schwartz; Ian Young; Douglas Easton; Martin Bobrow; P Andrew Futreal; Michael R Stratton; Jozef Gecz; Richard Wooster; F Lucy Raymond Journal: Am J Hum Genet Date: 2004-06-07 Impact factor: 11.025
Authors: Peter Szatmari; Andrew D Paterson; Lonnie Zwaigenbaum; Wendy Roberts; Jessica Brian; Xiao-Qing Liu; John B Vincent; Jennifer L Skaug; Ann P Thompson; Lili Senman; Lars Feuk; Cheng Qian; Susan E Bryson; Marshall B Jones; Christian R Marshall; Stephen W Scherer; Veronica J Vieland; Christopher Bartlett; La Vonne Mangin; Rhinda Goedken; Alberto Segre; Margaret A Pericak-Vance; Michael L Cuccaro; John R Gilbert; Harry H Wright; Ruth K Abramson; Catalina Betancur; Thomas Bourgeron; Christopher Gillberg; Marion Leboyer; Joseph D Buxbaum; Kenneth L Davis; Eric Hollander; Jeremy M Silverman; Joachim Hallmayer; Linda Lotspeich; James S Sutcliffe; Jonathan L Haines; Susan E Folstein; Joseph Piven; Thomas H Wassink; Val Sheffield; Daniel H Geschwind; Maja Bucan; W Ted Brown; Rita M Cantor; John N Constantino; T Conrad Gilliam; Martha Herbert; Clara Lajonchere; David H Ledbetter; Christa Lese-Martin; Janet Miller; Stan Nelson; Carol A Samango-Sprouse; Sarah Spence; Matthew State; Rudolph E Tanzi; Hilary Coon; Geraldine Dawson; Bernie Devlin; Annette Estes; Pamela Flodman; Lambertus Klei; William M McMahon; Nancy Minshew; Jeff Munson; Elena Korvatska; Patricia M Rodier; Gerard D Schellenberg; Moyra Smith; M Anne Spence; Chris Stodgell; Ping Guo Tepper; Ellen M Wijsman; Chang-En Yu; Bernadette Rogé; Carine Mantoulan; Kerstin Wittemeyer; Annemarie Poustka; Bärbel Felder; Sabine M Klauck; Claudia Schuster; Fritz Poustka; Sven Bölte; Sabine Feineis-Matthews; Evelyn Herbrecht; Gabi Schmötzer; John Tsiantis; Katerina Papanikolaou; Elena Maestrini; Elena Bacchelli; Francesca Blasi; Simona Carone; Claudio Toma; Herman Van Engeland; Maretha de Jonge; Chantal Kemner; Frederieke Koop; Frederike Koop; Marjolein Langemeijer; Marjolijn Langemeijer; Channa Hijmans; Channa Hijimans; Wouter G Staal; Gillian Baird; Patrick F Bolton; Michael L Rutter; Emma Weisblatt; Jonathan Green; Catherine Aldred; Julie-Anne Wilkinson; Andrew Pickles; Ann Le Couteur; Tom Berney; Helen McConachie; Anthony J Bailey; Kostas Francis; Gemma Honeyman; Aislinn Hutchinson; Jeremy R Parr; Simon Wallace; Anthony P Monaco; Gabrielle Barnby; Kazuhiro Kobayashi; Janine A Lamb; Ines Sousa; Nuala Sykes; Edwin H Cook; Stephen J Guter; Bennett L Leventhal; Jeff Salt; Catherine Lord; Christina Corsello; Vanessa Hus; Daniel E Weeks; Fred Volkmar; Maïté Tauber; Eric Fombonne; Andy Shih; Kacie J Meyer Journal: Nat Genet Date: 2007-02-18 Impact factor: 38.330
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Authors: Sheryl S Moy; Natallia V Riddick; Viktoriya D Nikolova; Brian L Teng; Kara L Agster; Randal J Nonneman; Nancy B Young; Lorinda K Baker; Jessica J Nadler; James W Bodfish Journal: Behav Brain Res Date: 2013-11-08 Impact factor: 3.332