GIRK1-Mediated Inwardly Rectifying Potassium Current Is a Candidate Mechanism Behind Purkinje Cell Excitability, Plastic
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ORIGINAL ARTICLE
GIRK1-Mediated Inwardly Rectifying Potassium Current Is a Candidate Mechanism Behind Purkinje Cell Excitability, Plasticity, and Neuromodulation Pellegrino Lippiello 1 & Eriola Hoxha 2,3 & Filippo Tempia 2,3,4 & Maria Concetta Miniaci 1
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract G-protein-coupled inwardly rectifying potassium (GIRK) channels contribute to the resting membrane potential of many neurons and play an important role in controlling neuronal excitability. Although previous studies have revealed a high expression of GIRK subunits in the cerebellum, their functional role has never been clearly described. Using patch-clamp recordings in mice cerebellar slices, we examined the properties of the GIRK currents in Purkinje cells (PCs) and investigated the effects of a selective agonist of GIRK1-containing channels, ML297 (ML), on PC firing and synaptic plasticity. We demonstrated that GIRK channel activation decreases the PC excitability by inhibiting both sodium and calcium spikes and, in addition, modulates the complex spike response evoked by climbing fiber stimulation. Our results indicate that GIRK channels have also a marked effect on synaptic plasticity of the parallel fiber-PC synapse, as the application of ML297 increased the expression of LTP while preventing LTD. We, therefore, propose that the recruitment of GIRK channels represents a crucial mechanism by which neuromodulators can control synaptic strength and membrane conductance for proper refinement of the neural network involved in memory storage and higher cognitive functions. Keywords Cerebellum . GIRK . Neuromodulation . Purkinje cell . Synaptic plasticity
Abbreviations GIRK G-protein-coupled inwardly rectifying potassium CF Climbing fiber LTD Long-term depression LTP Long-term potentiation EPSP Excitatory postsynaptic potential PC Purkinje cell Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12311-020-01158-y) contains supplementary material, which is available to authorized users. * Filippo Tempia [email protected] * Maria Concetta Miniaci [email protected] 1
Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
2
Department of Neuroscience, University of Turin, Turin, Italy
3
Neuroscience Institute Cavalieri Ottolenghi (NICO), Turin, Italy
4
National Institute of Neuroscience (INN), Turin, Italy
Introduction G-protein-coupled inwardly rectifying potassium (GIRK/Kir3) channels are widely expressed throughout the CNS where they contribute to the resting membrane potential and play an important role in regulating neuronal excitability [1, 2]. One of the main features of GIRK channels is that they can be activated by a variety of G-protein-coupled receptors, such as M2-muscarinic, α2-adrenergic, D2-dopaminergic, opioid, CB1 cannabinoid, and A1-adenosine receptors [3, 4]. GIRK channels can be also activated by ethanol independently of G-protein-coupled signaling pathways [3]. Recently, GI
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