Memantine alters striatal plasticity inducing a shift of synaptic responses toward long-term depression. (February 2016)

• Record Type: Journal Article
• Authors: Mancini, Maria; Ghiglieri, Veronica; Bagetta, Vincenza; Pendolino, Valentina; Vannelli, Anna; Cacace, Fabrizio; Mineo, Desireé; Calabresi, Paolo; Picconi, Barbara
• Is Part Of: Neuropharmacology. Volume 101(2016)
• Page Start: 341
• Page End: 350
• Publication Date: 2016-02
• Subjects: Memantine -- Striatum -- Synaptic plasticity -- LTP -- LTD -- NMDA receptor -- D2 receptor; SPNs spiny projection neurons -- LTP long-term potentiation -- LTD long-term depression -- NMDA N-Methyl-d-Aspartate -- HFS high frequency stimulation -- DA dopamine -- AD Alzheimer's disease -- PD Parkinson's disease -- SN substantia nigra -- aCSF artificial cerebrospinal fluid -- EPSP excitatory post synaptic potential -- Mem memantine hydrochloride -- MK801 (+)-MK-801 hydrogen maleate -- Quinp (−)-quinpirole hydrochloride -- CNQX 6-cyano-7-nitroquinoxaline-2, 3-dione -- APV R-2-amino-5-phosphonopentanoate -- Sulp (RS)-(±)-sulpiride -- DMSO dimethyl sulfoxide -- AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Memantine hydrochloride (PubChem CID:1814589) -- AM 251 (PubChem CID:2125) -- Sulpiride (PubChem CID:5355) -- (−)-Quinpirole (PubChem CID:55397); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2015.10.015
• Languages: English
• ISSNs: 0028-3908

Abstract

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. Highlights: Memantine elicits LTD instead of LTP after HFS of striatal spiny projection neurons. DA D2 receptor antagonist sulpiride prevents memantine-LTD and restores LTP. The application of D2 agonist quinpirole, similarly to memantine, induces LTD. Memantine-induced LTD is prevented by CB1 endocannabinoid receptor antagonism.