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Séminaire - Lorenzo CingolaniMatching channels to function: alternative splicing of voltage-gated calcium channels and presynaptic plasticity

Abstract :

 Alternative splicing of pre-mRNAs is prominent in the mammalian brain, where it is thought to expand proteome diversity.
For example, alternative splicing of calcium channel α1 subunits can potentially generate thousands of isoforms with differential properties and expression patterns. However, the impact of this molecular diversity on brain function, particularly on synaptic transmission that crucially depends on calcium channels, is not known. I will present recent findings on how alternative splicing of P/Q-type calcium channels can be used to regulate vesicle release and presynaptic plasticity at hippocampal synapses. By combining electrophysiological recordings with optogenetic stimulations, along with imaging of presynaptic calcium and vesicle turnover, we show that two mutually exclusive isoforms of P/Q-type calcium channels (Cav2.1[EFa] and Cav2.1[EFb]) regulate neurotransmitter release and short-term synaptic plasticity in opposite directions: Cav2.1[EFa] boosts synaptic efficacy and promotes synaptic depression while Cav2.1[EFb] tilts the balance towards low synaptic efficacy and synaptic facilitation. We find that hippocampal neurons regulate the synaptic balance between the two splice isoforms to adjust presynaptic strength to changes in network activity. Specifically, they up-regulate Cav2.1[EFa], the splice isoform exhibiting the highest synaptic efficacy, in response to a reduction in postsynaptic excitability, thus effectively supporting homeostatic synaptic plasticity. We propose that P/Q-type calcium channels do not constitute a uniform population with respect to their efficacy for eliciting vesicle release and that the differences in efficacy between P/Q-type calcium channel isoforms are key to controlling neurotransmitter release and presynaptic plasticity. I will conclude by highlighting current and future directions of this line of research.

Selected publications

  • Ronzitti, G., Bucci, G., Emanuele, M., Leo, D., Sotnikova, T.D., Mus, L.V., Soubrane, C.H., Dallas, M.L., Thalhammer, A., Cingolani, L.A., Mochida, S., Gainetdinov, R., Stephens, G., and Chieregatti, E. (2014). Exogenous alpha-Synuclein Decreases Raft Partitioning of Cav2.2 Channels Inducing Dopamine Release. J Neurosci 34, 10603-10615
  • Thalhammer, A., and Cingolani, L.A. (2014). Cell adhesion and homeostatic synaptic plasticity. Neuropharmacology 78, 23-30.
  •  Bassani, S., Cingolani, L. A., Valnegri, P., Folci A., Zapata, J., Gianfelice, A., Sala, C., Goda, Y., and Passafaro., M. (2012) TSPAN7, a protein involved in X-linked intellectual disability, promotes development of excitatory synapses and regulates AMPAR trafficking through interaction with PICK1. Neuron 73, 1143-1158.