Changuk Chung1, Seungmin Ha2, Hyojin Kang3, Jiseok Lee4, Seung Min Um2, Haidun Yan5, Ye-Eun Yoo2, Taesun Yoo2, Hwajin Jung4, Dongwon Lee4, Eunee Lee4, Seungjoon Lee2, Jihye Kim4, Ryunhee Kim2, Yonghan Kwon2, Woohyun Kim2, Hyosang Kim2, Lara Duffney5, Doyoun Kim4, Won Mah6, Hyejung Won7, Seojung Mo8, Jin Yong Kim8, Chae-Seok Lim9, Bong-Kiun Kaang9, Tobias M Boeckers10, Yeonseung Chung11, Hyun Kim8, Yong-Hui Jiang12, Eunjoon Kim13. 1. Department of Biological Sciences, South Korea; Center for Synaptic Brain Dysfunctions, Institute for Basic Science, South Korea. 2. Department of Biological Sciences, South Korea. 3. Department of Convergence Technology Research, Korea Institute of Science and Technology Information, Daejeon, South Korea. 4. Center for Synaptic Brain Dysfunctions, Institute for Basic Science, South Korea. 5. Department of Pediatrics, Duke University, Durham, North Carolina. 6. Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, South Korea. 7. Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 8. Department of Anatomy and Division of Brain Korea 21, Biomedical Science, College of Medicine, Korea University, Seoul, South Korea. 9. School of Biological Sciences, Seoul National University, Seoul, South Korea. 10. Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany. 11. Department of Mathematical Sciences, Korea Advanced Institute for Science and Technology, South Korea. 12. Department of Pediatrics, Duke University, Durham, North Carolina; Department of Neurobiology, Duke University, Durham, North Carolina; Cell and Molecular Biology Program, Duke University, Durham, North Carolina; Duke Institute of Brain Science, Duke University, Durham, North Carolina; Genomics and Genetics Program, Duke University, Durham, North Carolina. 13. Department of Biological Sciences, South Korea; Center for Synaptic Brain Dysfunctions, Institute for Basic Science, South Korea. Electronic address: kime@kaist.ac.kr.
Abstract
BACKGROUND: Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many autism spectrum disorder-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. METHODS: We used Shank2-/- mice carrying a mutation identified in human autism spectrum disorder (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice. RESULTS: Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2-/- mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype-NMDAR hyperfunction-at an earlier preweaning stage (∼P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDAR hypofunction after weaning (∼P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7-P21) prevents NMDAR hypofunction and autistic-like social behaviors from manifesting at later stages (∼P28 and P56). CONCLUSIONS: Early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like social behaviors in Shank2-/- mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like social behaviors from developing at later stages.
BACKGROUND:Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many autism spectrum disorder-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. METHODS: We used Shank2-/- mice carrying a mutation identified in humanautism spectrum disorder (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice. RESULTS: Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2-/- mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype-NMDAR hyperfunction-at an earlier preweaning stage (∼P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDARhypofunction after weaning (∼P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7-P21) prevents NMDARhypofunction and autistic-like social behaviors from manifesting at later stages (∼P28 and P56). CONCLUSIONS: Early NMDAR hyperfunction leads to late NMDARhypofunction and autistic-like social behaviors in Shank2-/- mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like social behaviors from developing at later stages.
Authors: Thomas C Jaramillo; Haley E Speed; Zhong Xuan; Jeremy M Reimers; Shunan Liu; Craig M Powell Journal: Autism Res Date: 2015-11-11 Impact factor: 5.216
Authors: Claire S Leblond; Caroline Nava; Anne Polge; Julie Gauthier; Guillaume Huguet; Serge Lumbroso; Fabienne Giuliano; Coline Stordeur; Christel Depienne; Kevin Mouzat; Dalila Pinto; Jennifer Howe; Nathalie Lemière; Christelle M Durand; Jessica Guibert; Elodie Ey; Roberto Toro; Hugo Peyre; Alexandre Mathieu; Frédérique Amsellem; Maria Rastam; I Carina Gillberg; Gudrun A Rappold; Richard Holt; Anthony P Monaco; Elena Maestrini; Pilar Galan; Delphine Heron; Aurélia Jacquette; Alexandra Afenjar; Agnès Rastetter; Alexis Brice; Françoise Devillard; Brigitte Assouline; Fanny Laffargue; James Lespinasse; Jean Chiesa; François Rivier; Dominique Bonneau; Beatrice Regnault; Diana Zelenika; Marc Delepine; Mark Lathrop; Damien Sanlaville; Caroline Schluth-Bolard; Patrick Edery; Laurence Perrin; Anne Claude Tabet; Michael J Schmeisser; Tobias M Boeckers; Mary Coleman; Daisuke Sato; Peter Szatmari; Stephen W Scherer; Guy A Rouleau; Catalina Betancur; Marion Leboyer; Christopher Gillberg; Richard Delorme; Thomas Bourgeron Journal: PLoS Genet Date: 2014-09-04 Impact factor: 5.917
Authors: Amita Shrestha; Razia Sultana; Philip A Adeniyi; Charles C Lee; Olalekan M Ogundele Journal: Dev Neurosci Date: 2020-06-24 Impact factor: 2.984
Authors: Sara C Taylor; Sarah L Ferri; Mahip Grewal; Zoe Smernoff; Maja Bucan; Joshua A Weiner; Ted Abel; Edward S Brodkin Journal: Biol Psychiatry Date: 2020-02-22 Impact factor: 12.810
Authors: Rosa Marotta; Maria C Risoleo; Giovanni Messina; Lucia Parisi; Marco Carotenuto; Luigi Vetri; Michele Roccella Journal: Brain Sci Date: 2020-03-13