Contrasting synaptic roles of MDGA1 and MDGA2

Bemben, M. A.; Sandoval, M. A.; Le, A. A.; Won, S.; Chau, V. N.; Lauterborn, J. C.; Incontro, S.; Li, K. H.; Burlingame, A. L.; Roche, K. W.; Gall, C. M.; Nicoll, R. A.; Diaz-Alonso, J.

doi:10.1101/2023.05.25.542333

bioRxiv · 10.1101/2023.05.25.542333

Contrasting synaptic roles of MDGA1 and MDGA2

Bemben, M. A.·Sandoval, M. A.·Le, A. A.·Won, S.·Chau, V. N.·Lauterborn, J. C.·Incontro, S.·Li, K. H.·Burlingame, A. L.·Roche, K. W.·Gall, C. M.·Nicoll, R. A.·Diaz-Alonso, J.

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Abstract

Neurodevelopmental disorders are frequently linked to mutations in synaptic organizing molecules. MAM domain containing glycosylphosphatidylinositol anchor 1 and 2 (MDGA1 and MDGA2) are a family of synaptic organizers suggested to play an unusual role as synaptic repressors, but studies offer conflicting evidence for their localization. Using epitope-tagged MDGA1 and MDGA2 knock-in mice, we found that native MDGAs are expressed throughout the brain, peaking early in postnatal development. Surprisingly, endogenous MDGA1 was enriched at excitatory, but not inhibitory, synapses. Both shRNA knockdown and CRISPR/Cas9 knockout of MDGA1 resulted in cell-autonomous, specific impairment of AMPA receptor- mediated synaptic transmission, without affecting GABAergic transmission. Conversely, MDGA2 knockdown/knockout selectively depressed NMDA receptor-mediated transmission but enhanced inhibitory transmission. Our results establish that MDGA2 acts as a synaptic repressor, but only at inhibitory synapses, whereas both MDGAs are required for excitatory transmission. This nonoverlapping division of labor between two highly conserved synaptic proteins is unprecedented. TeaserMDGAs 1 and 2 independently localize to and modulate excitatory and inhibitory hippocampal synapses by different mechanisms.

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Bemben, M. A., Sandoval, M. A., Le, A. A., Won, S., Chau, V. N., Lauterborn, J. C., Incontro, S., Li, K. H., Burlingame, A. L., Roche, K. W., Gall, C. M., Nicoll, R. A., Diaz-Alonso, J.. 2023-05-26. Contrasting synaptic roles of MDGA1 and MDGA2. https://doi.org/10.1101/2023.05.25.542333

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