--- res: bibo_abstract: - In nerve cells the genes encoding for α2δ subunits of voltage-gated calcium channels have been linked to synaptic functions and neurological disease. Here we show that α2δ subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular α2δ subunit triple-knockout/knockdown model, we demonstrate a failure in presynaptic differentiation evidenced by defective presynaptic calcium channel clustering and calcium influx, smaller presynaptic active zones, and a strongly reduced accumulation of presynaptic vesicle-associated proteins (synapsin and vGLUT). The presynaptic defect is associated with the downscaling of postsynaptic AMPA receptors and the postsynaptic density. The role of α2δ isoforms as synaptic organizers is highly redundant, as each individual α2δ isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Moreover, α2δ-2 and α2δ-3 with mutated metal ion-dependent adhesion sites can fully rescue presynaptic synapsin expression but only partially calcium channel trafficking, suggesting that the regulatory role of α2δ subunits is independent from its role as a calcium channel subunit. Our findings influence the current view on excitatory synapse formation. First, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Second, the dependence of presynaptic differentiation on α2δ implicates α2δ subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that α2δ subunits act as transsynaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.@eng bibo_authorlist: - foaf_Person: foaf_givenName: Clemens L. foaf_name: Schöpf, Clemens L. foaf_surname: Schöpf - foaf_Person: foaf_givenName: Cornelia foaf_name: Ablinger, Cornelia foaf_surname: Ablinger - foaf_Person: foaf_givenName: Stefanie M. foaf_name: Geisler, Stefanie M. foaf_surname: Geisler - foaf_Person: foaf_givenName: Ruslan I. foaf_name: Stanika, Ruslan I. foaf_surname: Stanika - foaf_Person: foaf_givenName: Marta foaf_name: Campiglio, Marta foaf_surname: Campiglio - foaf_Person: foaf_givenName: Walter foaf_name: Kaufmann, Walter foaf_surname: Kaufmann foaf_workInfoHomepage: http://www.librecat.org/personId=3F99E422-F248-11E8-B48F-1D18A9856A87 orcid: 0000-0001-9735-5315 - foaf_Person: foaf_givenName: Benedikt foaf_name: Nimmervoll, Benedikt foaf_surname: Nimmervoll - foaf_Person: foaf_givenName: Bettina foaf_name: Schlick, Bettina foaf_surname: Schlick - foaf_Person: foaf_givenName: Johannes foaf_name: Brockhaus, Johannes foaf_surname: Brockhaus - foaf_Person: foaf_givenName: Markus foaf_name: Missler, Markus foaf_surname: Missler - foaf_Person: foaf_givenName: Ryuichi foaf_name: Shigemoto, Ryuichi foaf_surname: Shigemoto foaf_workInfoHomepage: http://www.librecat.org/personId=499F3ABC-F248-11E8-B48F-1D18A9856A87 orcid: 0000-0001-8761-9444 - foaf_Person: foaf_givenName: Gerald J. foaf_name: Obermair, Gerald J. foaf_surname: Obermair bibo_doi: 10.1073/pnas.1920827118 bibo_issue: '14' bibo_volume: 118 dct_date: 2021^xs_gYear dct_identifier: - UT:000637398300002 dct_isPartOf: - http://id.crossref.org/issn/1091-6490 dct_language: eng dct_publisher: National Academy of Sciences@ dct_title: Presynaptic α2δ subunits are key organizers of glutamatergic synapses@ ...