Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2.
Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses. Behavioral assays revealed an autism-like phenotype including stereotypy, aberrant social interactions, and impaired memory. In vivo voltage-sensitive dye imaging, facilitating comparison with fMRI studies in autism, revealed widespread increases in cortical spontaneous activity and intracortical functional connectivity. These results suggest that mutations in MDGA2 contribute to altered cortical processing through the dual disadvantages of elevated excitation and hyperconnectivity, and indicate that perturbations of the NRXN-NLGN pathway in either direction from the norm increase risk for autism.
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Brain Research Centre and Department of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Steven A
SA
Connor
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Ina
I
Ammendrup-Johnsen
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Brain Research Centre and Department of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Allen W
AW
Chan
Department of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa 769-2101, Japan.
Yasushi
Y
Kishimoto
Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan; Laboratory of Neuroscience, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
Chiaki
C
Murayama
Department of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa 769-2101, Japan.
Naokazu
N
Kurihara
Department of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa 769-2101, Japan.
Atsushi
A
Tada
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Yuan
Y
Ge
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Hong
H
Lu
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Ryan
R
Yan
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Jeffrey M
JM
LeDue
Laboratory of Neuroscience, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
Hirotaka
H
Matsumoto
Animal Resource Development Unit, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan; Genetic Engineering Team, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan.
Hiroshi
H
Kiyonari
Department of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa 769-2101, Japan.
Yutaka
Y
Kirino
Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan.
Fumio
F
Matsuzaki
Laboratory of Neuroscience, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
Toshiharu
T
Suzuki
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Timothy H
TH
Murphy
Brain Research Centre and Department of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: ytwang@brain.ubc.ca.
Yu Tian
YT
Wang
Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa 761-0793, Japan. Electronic address: tohru@med.kagawa-u.ac.jp.
Tohru
T
Yamamoto
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: acraig@mail.ubc.ca.
Ann Marie
AM
Craig
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology*; D003071:Cognition / Q000502:physiology*; D000076122:Disks Large Homolog 4 Protein; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051528:Guanylate Kinases / Q000378:metabolism; D057895:Haploinsufficiency / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology; D019006:Neural Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism / Q000502:physiology; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
D015816:Cell Adhesion Molecules, Neuronal; D000076122:Disks Large Homolog 4 Protein; D058851:GPI-Linked Proteins; D051528:Guanylate Kinases; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D018091:Receptors, AMPA; C501447:Dlg4 protein, mouse; C571222:MDGA2 protein, mouse; C093438:neuroligin 1; C098003:neuroligin 2