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GIRK1-Mediated Inwardly Rectifying Potassium Current Is a Candidate Mechanism Behind Purkinje Cell Excitability, Plasticity, and Neuromodulation

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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.

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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

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Funding

This work was supported by a grant from Regione Campania—POR Campania FESR 2014/2020 (Project No. B61G18000470007) to M.C.M., by a grant of the University of Torino (Local Research Grant, FY 2018) to F.T., and by a donation in memory of Achille Barbetta. P.L. was supported by the Department of Pharmacy fellowship, funded by MIUR Department of excellence grant.

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Authors and Affiliations

  1. Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy

    Pellegrino Lippiello & Maria Concetta Miniaci

  2. Department of Neuroscience, University of Turin, Turin, Italy

    Eriola Hoxha & Filippo Tempia

  3. Neuroscience Institute Cavalieri Ottolenghi (NICO), Turin, Italy

    Eriola Hoxha & Filippo Tempia

  4. National Institute of Neuroscience (INN), Turin, Italy

    Filippo Tempia

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  1. Pellegrino Lippiello
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  2. Eriola Hoxha
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  3. Filippo Tempia
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  4. Maria Concetta Miniaci
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Contributions

Collection, analysis, and interpretation of data: P.L, E.H, F.T, and M.C.M. Drafting manuscript and graphical representation of data: P.L and E.H. Critical evaluation of manuscript: F.T and M.C.M. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

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Correspondence to Filippo Tempia or Maria Concetta Miniaci.

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Lippiello, P., Hoxha, E., Tempia, F. et al. GIRK1-Mediated Inwardly Rectifying Potassium Current Is a Candidate Mechanism Behind Purkinje Cell Excitability, Plasticity, and Neuromodulation. Cerebellum 19, 751–761 (2020). https://doi.org/10.1007/s12311-020-01158-y

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