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Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2.

Abstract：

: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.

journal_name

Neuron

journal_title

Neuron

authors

Connor SA,Ammendrup-Johnsen I,Chan AW,Kishimoto Y,Murayama C,Kurihara N,Tada A,Ge Y,Lu H,Yan R,LeDue JM,Matsumoto H,Kiyonari H,Kirino Y,Matsuzaki F,Suzuki T,Murphy TH,Wang YT,Yamamoto T,Craig AM

doi

10.1016/j.neuron.2016.08.016

subject

Has Abstract

pub_date

2016-09-07 00:00:00

pages

1052-1068

issue

5

eissn

0896-6273

issn

1097-4199

pii

S0896-6273(16)30508-6

journal_volume

91

pub_type

杂志文章

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