Evidence for Functionally Distinct Synaptic NMDA Receptors in Ventromedial Versus Dorsolateral Striatum

Abstract

N-methyl-D-aspartate receptors (NMDARs) are comprised of different subunits. NR2 subunits confer different pharmacological and biophysical properties to NMDARs. Although NR2B subunit expression is uniform throughout striatum, NR2A subunit expression is greater laterally. Pharmacologically isolated NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs) were elicited using minimal local stimulation and recorded in the whole cell configuration to test the hypothesis that biophysical and pharmacological properties of NMDAR-EPSCs of striatal neurons would vary as a function of their location in adult rat striatum. We observed that the decay-time kinetics of NMDAR-EPSCs are significantly slower in neurons of ventromedial versus dorsolateral striatum. Whereas ifenprodil did not differentially affect NMDAR-EPSCs in these regions, application of either glycine or D-serine increased the peak current of NMDAR-EPSCs selectively in dorsolateral striatum. These data provide evidence for functionally distinct NMDARs in the same neuron type in the same brain region of the adult rodent brain. These data thus suggest that the nature of synaptic processing of excitatory input is different in the ventromedial and dorsolateral striatum of the adult rodent brain, regions differentially involved in limbic versus sensorimotor processes, respectively.

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

“…By extension of previous findings (Chapman et al 2003;Li et al 2003Li et al , 2004, we used P6-8 and ϾP12 mice to examine the properties of NMDA receptors in wild-type MSNs in addition to mice of similar ages that were lacking either the NR2A or the NR2C subunit. Our findings show that the ratio of the NMDA to non-NMDA component of EPSCs decreases with development.…”

“…Furthermore, studies of functional properties of striatal NMDA receptors at excitatory synapses (Chapman et al 2003;Colwell et al 1998;Wirkner et al 2004) suggest changes occur around the end of the second postnatal week. At this time, rodents undergo major alterations in striatal anatomy and physiology including synapse, dendritic spine formation (Tepper et al 1998) and a shift in synaptic plasticity from long-term potentiation (LTP) to long-term depression (LTD) in the dorsolateral striatum (Partridge et al 2000).…”

“…Comparing the kinetics of NMDA-excitatory postsynaptic currents (EPSCs), Chapman et al (2003) reported a faster rate of decay in MSNs from the dorsolateral compared with ventromedial striatum in rats. A pharmacological analysis of these currents revealed that pure NR1/NR2A and NR1/NR2B heterodimeric assemblies were only partially involved in synaptic transmission and that their relative synaptic contribution changed during development.…”

Cocaine Enhances NMDA Receptor-Mediated Currents in Ventral Tegmental Area Cells via Dopamine D5Receptor-Dependent Redistribution of NMDA Receptors

“…Dimeric receptors containing NR1/NR2B have slower offset kinetics than receptors built of NR1/NR2A, whereas triheteromeric receptors containing both NR2A and NR2B subunits are characterized by intermediate properties, such as reduced sensitivity to selective NR2B antagonists but slow offset kinetics dominated by the presence of NR2B subunit (Plant et al, 1997;Vicini et al, 1998;Tovar and Westbrook, 1999). A previous study identified functionally different NMDARs in the ventromedial and the dorsolateral striatum on the basis of their different decay time kinetics (Chapman et al, 2003), related to previously observed regional difference in the expression of NR2A and NR2B subunits (Standaert et al, 1994). Figure 7C shows that decay time kinetics of NMDAR EPSCs recorded at ϩ40 mV in VTA neurons from young rats [postnatal day 21 (P21) to P29] were fitted with the double-exponential equation; to compare decay times between different experimental conditions, we calculated a weighted decay time constant ( w ) derived from the weighted mean of the fast and the slow time constants.…”

Parallel processing across neural systems: Implications for a multiple memory system hypothesis

“…Selective medial striatal lesions produce spatial learning deficits (Devan & White, 1999), and medial striatum preferentially receives limbic input (Groenewegen, Vermeulen-Van de Zee, te Kortschot, & Witter, 1987). Also, medial and lateral striatum possess different NMDA systems, suggesting different mechanisms of neuroplasticity (Chapman, Keefe, & Wilcox, 2003). Second, there are two routes by which hippocampal information may impact behavior in an experience-dependent way (Mizumori, Pratt, Cooper, & Guazzelli, 2002) one initially involving striatal circuitry and another passing through cortical circuitry involving the retrosplenial cortex and medial precentral cortex .…”