Ca_V2.1 α₁ Subunit Expression Regulates Presynaptic Ca_V2.1 Abundance and Synaptic Strength at a Central Synapse

The abundance of presynaptic Ca_V2 voltage-gated Ca²⁺ channels (Ca_V2) at mammalian active zones (AZs) regulates the efficacy of synaptic transmission. It is proposed that presynaptic Ca_V2 levels are saturated in AZs due to a finite number of slots that set Ca_V2 subtype abundance and that Ca_V2.1 cannot compete for Ca_V2.2 slots. However, at most AZs, Ca_V2.1 levels are highest and Ca_V2.2 levels are developmentally reduced. To investigate Ca_V2.1 saturation states and preference in AZs, we overexpressed the Ca_V2.1 and Ca_V2.2 α₁ subunits at the calyx of Held at immature and mature developmental stages. We found that AZs prefer Ca_V2.1 to Ca_V2.2. Remarkably, Ca_V2.1 α₁ subunit overexpression drove increased Ca_V2.1 currents and channel numbers and increased synaptic strength at both developmental stages examined. Therefore, we propose that Ca_V2.1 levels in the AZ are not saturated and that synaptic strength can be modulated by increasing Ca_V2.1 levels to regulate neuronal circuit output. VIDEO ABSTRACT.