title: Memantine alters striatal plasticity inducing a shift of synaptic responses toward long-term depression.
abstract: Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca(2+)) influx occurring in presence of moderately increased glutamate levels. At the same time, memantine has the ability to preserve the transient physiological activation of NMDA receptor, essential for learning and memory formation at synaptic level. In the present study we investigated the effects exerted by memantine on striatal synaptic plasticity in rat striatal spiny projection neurons (SPNs). In vitro application of memantine in striatal slices elicited a disruption of long-term potentiation (LTP) induction and maintenance, and revealed, in the majority of the recorded neurons, a long-term depression (LTD), whose amplitude was concentration-dependent (0.3-10 μM). Interestingly, preincubation with the dopamine (DA) D2 receptor antagonist sulpiride (10 μM) prevented memantine-induced LTD and restored LTP. Moreover, the DA D2 agonist quinpirole (10 μM), similarly to memantine, induced LTD in a subgroup of SPNs. In addition, memantine-induced LTD was also prevented by the CB1 endocannabinoid receptor antagonist AM 251 (1 μM). These results suggest that the actions exerted by memantine on striatal synaptic plasticity, and in particular the induction of LTD observed in SPNs, could be attributed to its ability to activate DA D2 receptors. By contrast, blockade of NMDA receptor is not involved in memantine-induced LTD since APV (30 μM) and MK801 (10 μM), two NMDA receptor antagonists, failed to induce this form of synaptic plasticity. Our data indicate that memantine could be used as treatment of neurological disorders in which DA D2 receptor represents a possible therapeutic target.
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, via del Fosso di Fiorano 64, 00143 Rome, Italy; Dipartimento di Filosofia, Scienze Sociali, Umane e della Formazione, Università degli Studi di Perugia, Piazza Ermini 1, 06123 Perugia, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Bagetta
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pendolino
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, via del Fosso di Fiorano 64, 00143 Rome, Italy; Università di Roma Tor Vergata, Facoltà di Medicina e Chirurgia, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Vannelli
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Cacace
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, via del Fosso di Fiorano 64, 00143 Rome, Italy; Università di Roma Tor Vergata, Facoltà di Medicina e Chirurgia, Rome, Italy.
authors.forename: Desireé
authors.initials: D
authors.lastname: Mineo
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, via del Fosso di Fiorano 64, 00143 Rome, Italy; Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, Via Gambuli, 06156 Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, via del Fosso di Fiorano 64, 00143 Rome, Italy. Electronic address: b.picconi@hsantalucia.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D008559:Memantine; D010852:Picrotoxin
keywords: (−)-Quinpirole (PubChem CID:55397); AM 251 (PubChem CID:2125); D2 receptor; LTD; LTP; Memantine; Memantine hydrochloride (PubChem CID:1814589); NMDA receptor; Striatum; Sulpiride (PubChem CID:5355); Synaptic plasticity