Open AccessPresynaptic α 2 δ subunits are key organizers of glutamatergic synapses
Author(s) -
Clemens L. Schöpf,
Cornelia Ablinger,
Stefanie M. Geisler,
Ruslan I. Stanika,
Marta Campiglio,
Walter A. Kaufmann,
Benedikt Nimmervoll,
Bettina Schlick,
Johannes Brockhaus,
Markus Missler,
Ryuichi Shigemoto,
Gerald J. Obermair
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1920827118
Subject(s) - glutamatergic , neurotransmission , synapse , neuroscience , excitatory postsynaptic potential , hippocampal formation , biology , silent synapse , microbiology and biotechnology , gene knockdown , ribbon synapse , voltage dependent calcium channel , glutamate receptor , chemistry , calcium , synaptic vesicle , biochemistry , receptor , gene , inhibitory postsynaptic potential , vesicle , organic chemistry , membrane
In nerve cells the genes encoding for α 2 δ subunits of voltage-gated calcium channels have been linked to synaptic functions and neurological disease. Here we show that α 2 δ subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular α 2 δ 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 α 2 δ isoforms as synaptic organizers is highly redundant, as each individual α 2 δ isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Moreover, α 2 δ-2 and α 2 δ-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 α 2 δ 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 α 2 δ implicates α 2 δ subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that α 2 δ subunits act as transsynaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.