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TitleAltered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2.
Publication TypeJournal Article
Year of Publication2016
AuthorsConnor, Steven A., Ina Ammendrup-Johnsen, Allen W. Chan, Yasushi Kishimoto, Chiaki Murayama, Naokazu Kurihara, Atsushi Tada, Yuan Ge, Hong Lu, Ryan Yan, Jeffrey M. LeDue, Hirotaka Matsumoto, Hiroshi Kiyonari, Yutaka Kirino, Fumio Matsuzaki, Toshiharu Suzuki, Timothy H. Murphy, Yu Tian Wang, Tohru Yamamoto, and Ann Marie Craig
Date Published2016 Sep 07

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.

Alternate JournalNeuron
PubMed ID27608760