In the mammalian brain, presynaptic CaV2.2 channels play a pivotal role for synaptic
transmission by mediating fast neurotransmitter exocytosis via influx of Ca2+ into the
active zone at the presynaptic terminal. The distribution and activity of CaV2.2 channels
at different synapses and maturity stages in the brain remains to be elucidated. In this
study, I first show high levels of CaV2.2 channels in mouse cortex and hippocampus
throughout development, persisting into adulthood. In contrast, CaV2.2 channels in the
cerebellum and brain stem decreased as the brain matured. I thereafter assessed CaV2.2
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. In this work I show that chronic silencing of
neuronal activity in mature hippocampal cultures resulted in elevated presynaptic Ca2+
transients, mediated by a 30 % increase in CaV2.2 channel levels at the presynapse.
Next, this work focussed on α2δ-1 subunits, important regulators of synaptic transmission
and CaV2.2 channel abundance at the presynaptic membrane. Here, I show that α2δ-1-
overexpression reduces the contribution of CaV2.2 channels to total Ca2+ flux without
altering the amplitude of the Ca2+ transients. Finally, levels of endogenous α2δ-1
decreased during homeostatic synaptic plasticity, whereas the overexpression of α2δ-1
prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study
reveals a key role for CaV2.2 channels and novel roles for α2δ-1 during plastic synaptic
adaptation
