title: Epilepsy, amyloid-β, and D1 dopamine receptors: a possible pathogenetic link?
abstract: Experimental and clinical observations indicate that amyloid-β1-42(Aβ1-42) peptide not only represents a major actor in neurodegenerative mechanisms but also induce hyperexcitation in individual neurons and neural circuits. In this abnormal excitability, possibly leading to seizures, the D1 dopamine (DA) receptors may play a role. Cerebrospinal fluid levels of Aβ1-42were measured in patients with late-onset epilepsy of unknown etiology. Moreover, the effect of amyloid peptide on the hippocampal epileptic threshold and synaptic plasticity and its link to D1 receptor function were tested in experimental mouse model of cerebral amyloidosis and in acute model of Aβ1-42-induced neurotoxicity. Among 272 evaluated epileptic patients, aged >55 years, 35 suffered from late-onset epilepsy of unknown etiology. In these subjects, cerebrospinal fluid Aβ1-42levels were measured. The effects of Aβ1-42, amyloid oligomers, and D1 receptor modulation on epileptic threshold were analyzed by electrophysiological recordings in the dentate gyrus of mice hippocampal slices. We found that Aβ1-42levels were significantly decreased in cerebrospinal fluid of patients with late-onset epilepsy of unknown etiology with respect to controls suggesting the cerebral deposition of this peptide in these patients. Aβ1-42enhanced epileptic activity in mice through a mechanism involving increased surface expression of D1 receptor, and this effect was mimicked by D1 receptor stimulation and blocked by SCH 23390, a D1 receptor antagonist. Aβ1-42may contribute to the pathophysiology of late-onset epilepsy of unknown origin. Our preclinical findings indicate that the D1 receptor is involved in mediating the epileptic effects of Aβ1-42. This novel link between Aβ1-42and D1 receptor signaling might represent a potential therapeutic target.
authors.affiliation: Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy. Electronic address: cinzia.costa@unipg.it.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Costa
authors.affiliation: Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Parnetti
authors.affiliation: Laboratory of Molecular Neuroscience, Department of Medicine, Campus Bio-Medico University, Rome, Italy; Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: D'Amelio
authors.affiliation: Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy; Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.affiliation: Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.affiliation: Neurophysiopathology Unit, Department of Systems Medicine, Sleep and Epilepsy Medicine Centre, Tor Vergata University and Hospital, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Romigi
authors.affiliation: Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Siliquini
authors.affiliation: Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Virve
authors.initials: V
authors.lastname: Cavallucci
authors.affiliation: Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Filippo
authors.affiliation: Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Petra
authors.initials: P
authors.lastname: Mazzocchetti
authors.affiliation: Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Liguori
authors.affiliation: Laboratory of Molecular Neuroscience, Department of Medicine, Campus Bio-Medico University, Rome, Italy; Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Nobili
authors.affiliation: Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Eusebi
authors.affiliation: Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy; Neurophysiopathology Unit, Department of Systems Medicine, Sleep and Epilepsy Medicine Centre, Tor Vergata University and Hospital, Rome, Italy.
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Mercuri
authors.affiliation: Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy; Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000209:etiology* / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D001552:Benzazepines; D010446:Peptide Fragments; D017447:Receptors, Dopamine D1; C534628:SCH 23390; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Aβ(1–42) oligomers; D1 dopamine receptor; Epileptic threshold; Seizures; Transgenic mice