Presynaptic α(2)δs specify synaptic gain, not synaptogenesis, in the mammalian brain.

The α(2)δs are a family of extracellular synaptic molecules that are auxiliary subunits of voltage-gated Ca(2+) channel (Ca(V)) complexes. They are linked to brain disorders and are drug targets. The α(2)δs are implicated in controlling synapse development and function through distinct Ca(V)-dependent and Ca(V)-independent pathways. However, the mechanisms of action remain enigmatic since synapses contain mixtures of α(2)δ isoforms in the pre- and postsynaptic compartments. We developed a triple conditional knockout mouse model and demonstrated the combined selective presynaptic ablation of α(2)δs in vivo in a developing mammalian glutamatergic synapse. We identified presynaptic α(2)δs as positive regulators of Munc13-1 levels, an essential neurotransmitter release protein. We found that mammalian synapse development, presynaptic Ca(V)2.1 organization, and the transsynaptic alignment of presynaptic release sites and postsynaptic glutamate receptors are independent of presynaptic α(2)δs. Therefore, our results define presynaptic α(2)δ regulatory roles and suggest a new α(2)δ role in controlling synaptic strength and plasticity.