NR2B-Containing Receptors Mediate Cross Talk among Hippocampal Synapses

Abstract

Under some conditions, synaptically released glutamate can exert long-range actions in the cortical microcircuitry. To what extent glutamate spillover leads to direct cross talk among individual synapses remains unclear. We recorded NMDAR-mediated EPSCs in acute hippocampal slices at 35°C by stimulating two independent pathways that converge on the same CA1 pyramidal cell. Activation of a conditioning pathway in the presence of the use-dependent blocker dizocilpine maleate (MK801) resulted in partial NMDA receptor (NMDAR) blockade in the other, silent pathway. This was accompanied by an increase in the rise time of the EPSCs in the conditioning (although not the silent) pathway, implying an increase in diffusional distance from release site to NMDARs. We estimated that up to ϳ30% of NMDARs contributing to EPSCs were activated by glutamate released from multiple synaptic sources; however, NMDARmediated synaptic cross talk was undetectable when NR2B subunit-containing receptors were blocked (but could be rescued by blocking glutamate uptake). We propose that NR2B-containing NMDARs can detect glutamate arising from multiple synapses, whereas NR2A-containing NMDARs only normally mediate direct synaptic transmission. These NMDAR isoforms thus play complementary roles in sensing global and local glutamate signals, respectively.

Visual Deprivation Modifies Both Presynaptic Glutamate Release and the Composition of Perisynaptic/Extrasynaptic NMDA Receptors in Adult Visual Cortex

“…Previous studies demonstrate that glutamate spillover increases with EPSC size (Scimemi et al, 2004); that is, spillover is more likely to occur with an increase in the number of simultaneously activated synapses.…”

“…Because high-frequency stimulation additively can facilitate diffusion of glutamate at synapses and induce activation of perisynaptic/extrasynaptic NMDARs that are not activated by a single pulse (Scimemi et al, 2004), we reasoned that the enhanced temporal summation of NMDAR-mediated currents in deprived mice could be a consequence of glutamate spillover onto a modified population of perisynaptic/extrasynaptic NMDARs. Previous studies demonstrate that glutamate spillover increases with EPSC size (Scimemi et al, 2004); that is, spillover is more likely to occur with an increase in the number of simultaneously activated synapses.…”

Hallucinogen-Induced UP States in the Brain Slice of Rat Prefrontal Cortex: Role of Glutamate Spillover and NR2B-NMDA Receptors

“…Since recent studies in the adult rat have suggested that extrasynaptic glutamate transmission is mediated disproportionately by NMDA receptors that contain the NR2B subunit (Lozovaya et al, 2004;Scimemi et al, 2004), we assessed the ability of the selective NR2B antagonists Ro25-6981 (Fischer et al, 1997) and ifenprodil (Williams, 1993) to suppress DOI-enhanced late EPSCs. As shown in Figure 4, the late EPSC was markedly suppressed by either Ro25-6981 (500 nM, 10 min) or ifenprodil (3 mM, 10 min).…”

“…A growing body of literature suggests that activation of high-affinity extrasynaptic NMDA receptors by glutamatergic spillover may play a significant role in the brain function (Kullmann et al, 1996;Barbour and Hausser, 1997;Rusakov and Kullmann, 1998;Scimemi et al, 2004;Lozovaya et al, 2004). According to this view, the activation of any one synapse would not only activate its immediate postsynaptic partner, but may alsoFdepending on conditionsFbe able to activate high-affinity NMDA receptors at adjacent spines or presynaptic terminals.…”

“…While the diffusion of glutamate appears highly regulated by glial and neuronal uptake mechanisms (reviewed in Huang and Bergles, 2004), dendritic spines in the cerebral cortex are unusual in their relative lack of glial cover (Spacek, 1985). Since spillover would preferentially activate high-affinity NMDA receptors, it has been suggested that under normal physiological conditions it would not interfere with fast point-to-point transmission but instead may enhance responsiveness of the network (Shu et al, 2003;Scimemi et al, 2004). In fact, there are aspects of the subjective effects of psychedelic hallucinogens that appear consistent with enhancing interactions between synapses that would normally not experience 'cross talk,'Fthat is, altered sensory perception, increased emotional lability, and disturbed cognitive processing.…”