Long-Lasting NMDA Receptor-Mediated EPSCs in Mouse Striatal Medium Spiny Neurons

Abstract

Excitatory postsynaptic currents (EPSCs) from dorsolateral medium spiny neurons (MSNs) were recorded in cortico-striatal slice preparations from postnatal day 6-8 (P6-8) and >P12 wild-type mice and mice that were lacking either the NR2A or the NR2C subunit of the N-methyl-D-aspartate (NMDA) receptor. EPSCs were elicited by stimulation of the excitatory afferents and the NMDA and non-NMDA receptor-mediated components were pharmacologically isolated. The ratio of these components decreased with development and was significantly reduced only between age-matched +/+ and NR2A -/- neurons. In many MSNs, the NMDA-EPSC decay was characterized by the presence of a slow exponential component with a time constant lasting >1 s regardless of genotype or age. In the NR2A -/-, no developmental increase in the decay time (Tw) of the NMDA-EPSCs was observed although it was almost twofold longer than in +/+ MSNs. NR1/NR2B antagonists were ineffective in reducing the slow NMDA-EPSCs at all ages. Input-output studies revealed differences in stimulation threshold sensitivity of MSNs based on stimulus location. High-threshold responders were preferentially identified with stimulation from intracortical locations that produced considerably faster NMDA-EPSCs, whereas low-threshold responders were mainly elicited with stimulation more proximal to the striatum and exhibited slower NMDA-EPSCs. A low-affinity competitive antagonist of NMDA receptors failed to alter the decay of NMDA-EPSCs elicited from either location, suggesting that glutamate spillover is not responsible for the long-lasting NMDA-EPSCs. Our data are consistent with the expression of a unique NMDA receptor complex in MSNs with very slow deactivation kinetics.