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Neurobiol Dis. 2015 Jun;78:146-61. doi: 10.1016/j.nbd.2015.03.021. Epub 2015 Mar 26.

Rhes regulates dopamine D2 receptor transmission in striatal cholinergic interneurons.

Author information

1
Department of Systems Medicine, University of Rome "Tor Vergata", Via Oxford 1, 00133 Rome, Italy; IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Synaptic Plasticity, Via del Fosso di Fiorano 64, 00133 Rome, Italy.
2
Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy; CEINGE Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy.
3
Department of Biology, University of Pisa, Via L. Ghini 13, 56126 Pisa, Italy.
4
IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Synaptic Plasticity, Via del Fosso di Fiorano 64, 00133 Rome, Italy.
5
CEINGE Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy; Department of Health and Motor Sciences, DiSMeB, University of Naples "Parthenope", Via Medina 40, 80143, Naples, Italy.
6
CEINGE Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy.
7
Department of Philosophy and Human Sciences, University of Perugia, Piazza Ermini 1, 06123 Perugia (PG), Italy.
8
Department of Biology, University of Pisa, Via L. Ghini 13, 56126 Pisa, Italy; Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Corso Bettini 31, 38068 Rovereto (TN), Italy.
9
Department of Systems Medicine, University of Rome "Tor Vergata", Via Oxford 1, 00133 Rome, Italy; IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Synaptic Plasticity, Via del Fosso di Fiorano 64, 00133 Rome, Italy. Electronic address: pisani@uniroma2.it.
10
CEINGE Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy; Department of Environmental Sciences, Second University of Naples (SUN), Via Vivaldi 43, 81100 Caserta, Italy. Electronic address: usiello@ceinge.unina.it.

Abstract

Ras homolog enriched in striatum (Rhes) is highly expressed in striatal medium spiny neurons (MSNs) of rodents. In the present study, we characterized the expression of Rhes mRNA across species, as well as its functional role in other striatal neuron subtypes. Double in situ hybridization analysis showed that Rhes transcript is selectively localized in striatal cholinergic interneurons (ChIs), but not in GABAergic parvalbumin- or in neuropeptide Y-positive cell populations. Rhes is closely linked to dopamine-dependent signaling. Therefore, we recorded ChIs activity in basal condition and following dopamine receptor activation. Surprisingly, instead of an expected dopamine D2 receptor (D2R)-mediated inhibition, we observed an aberrant excitatory response in ChIs from Rhes knockout mice. Conversely, the effect of D1R agonist on ChIs was less robust in Rhes mutants than in controls. Although Rhes deletion in mutants occurs throughout the striatum, we demonstrate that the D2R response is altered specifically in ChIs, since it was recorded in pharmacological isolation, and prevented either by intrapipette BAPTA or by GDP-β-S. Moreover, we show that blockade of Cav2.2 calcium channels prevented the abnormal D2R response. Finally, we found that the abnormal D2R activation in ChIs was rescued by selective PI3K inhibition thus suggesting that Rhes functionally modulates PI3K/Akt signaling pathway in these neurons. Our findings reveal that, besides its expression in MSNs, Rhes is localized also in striatal ChIs and, most importantly, lack of this G-protein, significantly alters D2R modulation of striatal cholinergic excitability.

KEYWORDS:

Calcium; Cholinergic interneurons; D2 dopamine receptors; Dystonia; Rhes; Striatum

PMID:
25818655
DOI:
10.1016/j.nbd.2015.03.021
[Indexed for MEDLINE]

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