Involvement of Ca V 2.2 channels and α 2 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 Ca 2+ 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 Ca 2+ transients, mediated by increased levels of Ca V 2.2 channels at the presynaptic site. This work focused further on the role of α 2 δ-1 subunits, important regulators of synaptic transmission and Ca V 2.2 channel abundance at the presynaptic membrane. We found that α 2 δ-1 overexpression reduces the contribution of Ca V 2.2 channels to total Ca 2+ flux without altering the amplitude of the Ca 2+ transients. Levels of endogenous α 2 δ-1 decreased during homeostatic synaptic plasticity, whereas the overexpression of α 2 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 α 2 δ-1 during synaptic plastic adaptation. KEY POINTS: The roles of Ca V 2.2 channels and α 2 δ-1 in homeostatic synaptic plasticity in hippocampal neurons in culture were examined. Chronic silencing of neuronal activity resulted in elevated presynaptic Ca 2+ transients, mediated by increased levels of Ca V 2.2 channels at presynaptic sites. The level of endogenous α 2 δ-1 decreased during homeostatic synaptic plasticity, whereas overexpression of α 2 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 α 2 δ-1 during synaptic plastic adaptation.