Presynaptic α2δ subunits are key organizers of glutamatergic synapses

In nerve cells the genes encoding for 2{delta} subunits of voltage-gated calcium channels (VGCCs) have been linked to synaptic functions and neurological disease. Here we show that 2{delta} subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular 2{delta} subunit triple loss-of-function model, we demonstrate a failure in presynaptic differentiation associated with the downscaling of postsynaptic AMPA receptors and the postsynaptic density. The role of 2{delta} isoforms as synaptic organizers is highly redundant, as each individual 2{delta} isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Mutating the MIDAS site in 2{delta}-2 dissociates rescuing presynaptic synapsin expression from calcium channel trafficking, suggesting that the regulatory role of 2{delta} subunits is independent from its role as a calcium channel subunit. Our findings influence the current view on excitatory synapse formation. Firstly, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Secondly, the dependence of presynaptic differentiation on 2{delta} implicates 2{delta} subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that 2{delta} subunits act as trans-synaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.