Functional coupling of diverse voltage-gated Ca2+ channels underlies high fidelity of fast dendritic Ca2+ signals during burst firing

Abstract

Key points: In neurons, the Ca2+ signal associated with the dendritic back-propagating action potential codes a chemical message to the different dendritic sites, playing a crucial role in electrical signalling, synaptic transmission and synaptic plasticity. The study of the underlying Ca2+ current, mediated by different types of voltage-gated Ca2+ channels, cannot be achieved by using the patch clamp technique. In this article, we used a recently developed cutting-edge optical technique to investigate the physiological behaviour of local Ca2+ currents along the apical dendrite of CA1 hippocampal pyramidal neurons. We directly measure, for the first time, the synergistic activation and deactivation of the diverse dendritic voltage-gated Ca2+ channels operating during bursts of back-propagating action potentials to precisely control the Ca2+ signal. We demonstrate that the Ca2+ loss via high-voltage-activated channels is compensated by the Ca2+ entry via the other channels translating in high fidelity of Ca2+ signalling. In CA1 hippocampal pyramidal neurons, the dendritic Ca2+ signal associated with somatic firing represents a fundamental activation code for several proteins. This signal, mediated by voltage-gated Ca2+ channels (VGCCs), varies along the dendrites. In this study, using a recent optical technique based on the low-affinity indicator Oregon Green 488 BAPTA-5N, we analysed how activation and deactivation of VGCCs produced by back-propagating action potentials (bAPs) along the apical dendrite shape the Ca2+ signal at different locations in CA1 hippocampal pyramidal neurons of the mouse. We measured, at multiple dendritic sites, the Ca2+ transients and the changes in membrane potential associated with bAPs at 50 μs temporal resolution and we estimated the kinetics of the Ca2+ current. We found that during somatic bursts, the bAPs decrease in amplitude along the apical dendrite but the amplitude of the associated Ca2+ signal in the initial 200 μm dendritic segment does not change. Using a detailed pharmacological analysis, we demonstrate that this effect is due to the perfect compensation of the loss of Ca2+ via high-voltage-activated (HVA) VGCCs by a larger Ca2+ component via low-voltage-activated (LVA) VGCCs, revealing a mechanism coupling the two VGCC families of K+ channels. More distally, where the bAP does not activate HVA-VGCCs, the Ca2+ signal is variable during the burst. Thus, we demonstrate that HVA- and LVA-VGCCs operate synergistically to stabilise Ca2+ signals associated with bAPs in the most proximal 200 μm dendritic segment.