Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development.
Rare variants in MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors), including multiple protein-truncating deletions, are linked to autism and schizophrenia, but the function of these genes is poorly understood. Here, we show that MDGA1 and MDGA2 bound to neuroligin-2 inhibitory synapse-organizing protein, also implicated in neurodevelopmental disorders. MDGA1 inhibited the synapse-promoting activity of neuroligin-2, without altering neuroligin-2 surface trafficking, by inhibiting interaction of neuroligin-2 with neurexin. MDGA binding and suppression of synaptogenic activity was selective for neuroligin-2 and not neuroligin-1 excitatory synapse organizer. Overexpression of MDGA1 in cultured rat hippocampal neurons reduced inhibitory synapse density without altering excitatory synapse density. Furthermore, RNAi-mediated knockdown of MDGA1 selectively increased inhibitory but not excitatory synapse density. These results identify MDGA1 as one of few identified negative regulators of synapse development with a unique selectivity for inhibitory synapses. These results also place MDGAs in the neurexin-neuroligin synaptic pathway implicated in neurodevelopmental disorders and support the idea that an imbalance between inhibitory and excitatory synapses may contribute to these disorders.
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
Katherine L
KL
Pettem
Daisaku
D
Yokomaku
Hideto
H
Takahashi
Yuan
Y
Ge
Ann Marie
AM
Craig
D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism*; D019556:COS Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003712:Dendrites / Q000378:metabolism; D058851:GPI-Linked Proteins; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D009433:Neural Inhibition; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D011994:Recombinant Proteins; D013569:Synapses / Q000378:metabolism*
D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; C486864:MDGA1 protein, rat; C571222:MDGA2 protein, mouse; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D011994:Recombinant Proteins; C093438:neuroligin 1; C098003:neuroligin 2; C086959:neurexin Ibeta