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GIRK channels modulate Purkinje cell excitability and synaptic transmission in mice cerebellum

Pellegrino Lippiello1, Concetta Perreca1, Valentina Di Donna1, Eriola Hoxha2, Filippo Tempia2 and Maria Concetta Miniaci1*
  • 1 University of Naples Federico II, Department of Pharmacy, Italy
  • 2 University of Torino, Department of Neuroscience, Italy

The cerebellum is the brain region with the highest density of G-protein-coupled inwardly rectifying potassium (GIRK) channels that arise from the heteromeric assembly of different subunits (GIRK 1, GIRK2 and GIRK3). In Purkinje cells (PCs), GIRK channels are primarily localized on dendritic spines and the extrasynaptic plasma membrane of dendritic spines (Aguado et al., 2008; Alacid et al., 2009). Although previous studies have revealed the expression of GIRK subunits on Purkinje neurons, their functional role has never been clearly described. In this study, we examined the effects of a potent and selective agonist of GIRK1-containing channels, ML-297 (ML), on the intrinsic membrane properties and firing patterns of Purkinje cells (PCs), by using patch-clamp recordings in cerebellar slices of adult mice. We found that bath application of ML induced hyperpolarization of the PC cell membrane and a significant reduction of PC firing. These results are in accordance with previous studies demonstrating a critical role of GIRK channels in the modulation of the neural resting membrane potential and excitability. To determine whether the activation of GIRK channels plays a role in the modulation of the PF-PC synapse, we examined the effect of ML on the excitatory postsynaptic potentials (EPSPs) evoked by parallel fiber stimulation. We found that ML did not alter the amplitude of PF-EPSPs. On the contrary, activation of GIRK1-containing channels by ML was associated to a significant reduction of the complex spike response evoked by climbing fiber stimulation. Having shown that GIRK activation modulates the CF-PC synapses, we next assessed whether such effects can alter the expression and/or maintenance of PF-PC synaptic plasticity. Interestingly, we found that activation of GIRK channels blocked the expression of long-term depression (LTD) of the PF-PC synapse produced by pairing PF stimulation with PC depolarization, mimicking the CF stimulation. On the other hand, GIRK activation result in a significant increase of long-term potentiation (LTP) of PF-PC synapse induced by tetanic stimulation of parallel fibers. These findings indicate that GIRK channels regulate the ability of PF-PC to undergo synaptic plasticity. Since several neuromodulators can potentially activate GIRK channels by stimulating the G protein-coupled receptors (Lüscher and Slesinger, 2010), we finally examined the possible involvement of GIRK channels in the 2-adrenergic-mediated depression of PF-PC synapse (Lippiello et al., 2006). In the presence of the GIRK antagonist tertiapin, the 2-adrenergic agonist phenylephrine failed to depress the PF-PC synapses suggesting that GIRK channels are enrolled by adrenergic receptors. Altogether, our results indicate that GIRK channels shape the cerebellar neuronal network activity by regulating PC excitability and synaptic plasticity.

References

Aguado C, Colón J, Ciruela F, et al. Cell type-specific subunit composition of G protein-gated potassium channels in the cerebellum. J. Neurochem. 2008;105:497–511;
Fernández-Alacid L, Aguado C, Ciruela F, et al. Subcellular compartment-specific molecular diversity of pre- and postsynaptic GABAB-activated GIRK channels in Purkinje cells. Journal of neurochemistry. 2009;110(4):1363-1376. doi:10.1111/j.1471-4159.2009.06229.x.
Lippiello P, Hoxha E, Volpicelli F, Lo Duca G, Tempia F, Miniaci MC. Noradrenergic modulation of the parallel fiber-Purkinje cell synapse in mouse cerebellum. Neuropharmacology. 2014 Sep 9;89C:33-42. doi: 10.1016/j.neuropharm.2014.08.016.
Lüscher C, Slesinger PA. Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat Rev Neurosci 2010; 11(5): 301-15.

Keywords: GIRK, Purkinje, parallel fiber, climbing fibers, Cerebral Cortex, plasticity

Conference: The Cerebellum inside out: cells, circuits and functions , ERICE (Trapani), Italy, 1 Dec - 5 Dec, 2016.

Presentation Type: poster

Topic: Cellular & Molecular Neuroscience

Citation: Lippiello P, Perreca C, Di Donna V, Hoxha E, Tempia F and Miniaci M (2019). GIRK channels modulate Purkinje cell excitability and synaptic transmission in mice cerebellum. Conference Abstract: The Cerebellum inside out: cells, circuits and functions . doi: 10.3389/conf.fncel.2017.37.00008

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Received: 30 Nov 2016; Published Online: 25 Jan 2019.

* Correspondence: Prof. Maria Concetta Miniaci, University of Naples Federico II, Department of Pharmacy, Naples, Na, 80131, Italy, maria.miniaci@unina.it