title: Functional alterations of the dopaminergic and glutamatergic systems in spontaneous α-synuclein overexpressing rats.
abstract: The presence of α-synuclein (α-syn) in Lewy bodies and Lewy neurites is an important characteristic of the neurodegenerative processes of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons in Parkinson's disease (PD) and other synucleinopathies. Here we report that Berlin-Druckrey rats carrying a spontaneous mutation in the 3' untranslated region of α-syn mRNA (m/m rats) display a marked accumulation of α-syn in the mesencephalic area, striatum and frontal cortex, accompanied to severe dysfunctions in the dorsolateral striatum. Despite a small reduction in the number of SNpc and ventral tegmental area DAergic cells, the surviving dopaminergic neurons of the m/m rats do not show clear-cut alterations of the spontaneous and evoked firing activity, DA responses and somatic amphetamine-induced firing inhibition. Interestingly, mutant DAergic neurons display diminished whole-cell Ih conductance and a reduced frequency of spontaneous excitatory synaptic currents. By contrast, m/m rats show a severe impairment of DA and glutamate release in the dorsolateral striatum, as revealed by amperometric measure of DA currents and by electrophysiological recordings of glutamatergic synaptic events in striatal medium spiny neurons. These functional impairments are paralleled by a decreased expression of the DA transporter and VGluT1 proteins in the same area. Thus, together with α-syn overload in the mesencephalic region, striatum and frontal cortex, the main functional alterations occur in the DAergic and glutamatergic terminals in the dorsal striatum of the m/m rats.
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy; University Parthenope, Department of Motor Science and Wellness, Via Medina 40, 80133 Naples, Italy. Electronic address: e.guatteo@hsantalucia.it.
authors: Ezia
authors: E
authors: Guatteo
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy; University of Tor Vergata, Department of Systems Medicine, Via Montpellier 1, 00133 Rome, Italy. Electronic address: rizzo.francescaromana@gmail.com.
authors: Francesca Romana
authors: FR
authors: Rizzo
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy. Electronic address: m.federici@hsantalucia.it.
authors: Mauro
authors: M
authors: Federici
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy; University of Tor Vergata, Department of Systems Medicine, Via Montpellier 1, 00133 Rome, Italy. Electronic address: alberto_cordella@live.it.
authors: Alberto
authors: A
authors: Cordella
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy. Electronic address: adaledonne@gmail.com.
authors: Ada
authors: A
authors: Ledonne
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy. Electronic address: l.latini@hsantalucia.it.
authors: Laura
authors: L
authors: Latini
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy; University Campus Bio-Medico, Department of Medicine, Unit of Molecular Neurosciences, Rome, Italy. Electronic address: nobili.annalisa@gmail.com.
authors: Annalisa
authors: A
authors: Nobili
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy. Electronic address: mt.viscomi@hsantalucia.it.
authors: Maria Teresa
authors: MT
authors: Viscomi
authors: Catholic University of the Sacred Heart, Institute of Histology and Embryology, Largo F. Vito 1, 00168 Rome, Italy. Electronic address: filippo.biamonte@rm.unicatt.it.
authors: Filippo
authors: F
authors: Biamonte
authors: Texas A&M University, Department of Veterinary Pathobiology, College Station, TX, USA. Electronic address: KLandrock@cvm.tamu.edu.
authors: Kerstin K
authors: KK
authors: Landrock
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy; University of Tor Vergata, Department of Systems Medicine, Via Montpellier 1, 00133 Rome, Italy. Electronic address: alex1martini@hotmail.com.
authors: Alessandro
authors: A
authors: Martini
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy; University of Tor Vergata, Department of Systems Medicine, Via Montpellier 1, 00133 Rome, Italy. Electronic address: daniela.biotech@gmail.com.
authors: Daniela
authors: D
authors: Aversa
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy. Electronic address: chiara.schepisi@gmail.com.
authors: Chiara
authors: C
authors: Schepisi
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy; University Campus Bio-Medico, Department of Medicine, Unit of Molecular Neurosciences, Rome, Italy. Electronic address: m.damelio@hsantalucia.it.
authors: Marcello
authors: M
authors: D'Amelio
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy. Electronic address: n.berretta@hsantalucia.it.
authors: Nicola
authors: N
authors: Berretta
authors: Fondazione Santa Lucia IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy; University of Tor Vergata, Department of Systems Medicine, Via Montpellier 1, 00133 Rome, Italy. Electronic address: mercurin@med.uniroma2.it.
authors: Nicola B
authors: NB
authors: Mercuri
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D002452:Cell Count; D004298:Dopamine / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008636:Mesencephalon / Q000166:cytology*; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D055366:Synaptic Potentials / Q000187:drug effects; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D001640:Bicuculline; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D018698:Glutamic Acid; D010852:Picrotoxin; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D051844:alpha-Synuclein
keywords: Amperometry; DAergic terminals; Dopaminergic neurons; Dorsal striatum; Electrophysiology; Glutamatergic terminals; Lewy bodies dementia; Mutated rats; Parkinson's disease; Substantia nigra; Synaptic release; α-synuclein