Involvement of Ca_V 2.2 channels and α₂ δ-1 in homeostatic synaptic plasticity in cultured hippocampal neurons

In the mammalian brain, presynaptic Ca_V 2 channels play a pivotal role in synaptic transmission by mediating fast neurotransmitter exocytosis via influx of Ca²⁺ into the active zone of presynaptic terminals. However, the distribution and modulation of Ca_V 2.2 channels at plastic hippocampal synapses remains to be elucidated. Here, we assess Ca_V 2.2 channels during homeostatic synaptic plasticity, a compensatory form of homeostatic control preventing excessive or insufficient neuronal activity during which extensive active zone remodelling has been described. We show that chronic silencing of neuronal activity in mature hippocampal cultures resulted in elevated presynaptic Ca²⁺ transients, mediated by increased levels of Ca_V 2.2 channels at the presynaptic site. This work focused further on the role of α₂ δ-1 subunits, important regulators of synaptic transmission and Ca_V 2.2 channel abundance at the presynaptic membrane. We found that α₂ δ-1 overexpression reduces the contribution of Ca_V 2.2 channels to total Ca²⁺ flux without altering the amplitude of the Ca²⁺ transients. Levels of endogenous α₂ δ-1 decreased during homeostatic synaptic plasticity, whereas the overexpression of α₂ δ-1 prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study reveals a key role for Ca_V 2.2 channels and novel roles for α₂ δ-1 during synaptic plastic adaptation. KEY POINTS: The roles of Ca_V 2.2 channels and α₂ δ-1 in homeostatic synaptic plasticity in hippocampal neurons in culture were examined. Chronic silencing of neuronal activity resulted in elevated presynaptic Ca²⁺ transients, mediated by increased levels of Ca_V 2.2 channels at presynaptic sites. The level of endogenous α₂ δ-1 decreased during homeostatic synaptic plasticity, whereas overexpression of α₂ δ-1 prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study reveals a key role for Ca_V 2.2 channels and novel roles for α₂ δ-1 during synaptic plastic adaptation.