TY - JOUR
T1 - Memantine alters striatal plasticity inducing a shift of synaptic responses toward long-term depression
AU - Mancini, Maria
AU - Ghiglieri, Veronica
AU - Bagetta, Vincenza
AU - Pendolino, Valentina
AU - Vannelli, Anna
AU - Cacace, Fabrizio
AU - Mineo, Desireé
AU - Calabresi, Paolo
AU - Picconi, Barbara
PY - 2015/12/3
Y1 - 2015/12/3
N2 - Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca2+) 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.
AB - Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca2+) 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.
KW - D2 receptor
KW - LTD
KW - LTP
KW - Memantine
KW - NMDA receptor
KW - Striatum
KW - Synaptic plasticity
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U2 - 10.1016/j.neuropharm.2015.10.015
DO - 10.1016/j.neuropharm.2015.10.015
M3 - Article
AN - SCOPUS:84944755262
VL - 101
SP - 341
EP - 350
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
ER -