NR2B-Containing NMDA Autoreceptors at Synapses on Entorhinal Cortical Neurons

Woodhall, Gavin L.; Evans, D. Ieuan; Cunningham, Mark O.; Jones, Roland S.G.

doi:10.1152/jn.2001.86.4.1644

Cited by 120 publications

(151 citation statements)

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“…This observation is also not unexpected, since NR2A and NR2B subunits have been seen presynaptically (Charton et al, 1999;Conti et al, 1999;Valtschanoff and Weinberg, 2001). Moreover, electrophysiological studies have shown that these presynaptic receptors function as autoreceptors, facilitating glutamate release (Berretta and Jones, 1996;Woodhall et al, 2001). …”

Section: Discussion Nr2b Subunits Occur Both Pre-and Post-synapticallymentioning

confidence: 71%

In vivo blockade of N-methyl-d-aspartate receptors induces rapid trafficking of NR2B subunits away from synapses and out of spines and terminals in adult cortex

Fujisawa

Aoki

2003

Neuroscience

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We investigated the role of in vivo synaptic activity upon trafficking of the N-methyl-D-aspartate (NMDA) receptor subunit, NR2B, at mature synapses by electron microscopic immunocytochemistry. In vivo blockade of NMDA receptors was achieved by applying the NMDA receptor antagonist, D-2-amino-5-phosphonovalerate (D-APV), onto the cortical surface of one hemisphere of anesthetized adult rats. Inactive L-2-amino-5-phosphonovalerate (L-APV) was applied to the contralateral hemisphere for within-animal control and to assess basal level of NR2B subunits at synapses. Within 30 min of D-APV treatment, we observed a decrease in the number of layer I axospinous asymmetric synapses that are positively immuno-labeled for the NR2B subunits. This decrease was paralleled by reductions in the absolute number of immuno-gold particles found at these synapses. The decrease of NR2B labeling was detectable in all five animals examined. Significant reductions were seen not only at post-synaptic densities, but also within the cytoplasm of spines and axon terminals. The data demonstrate that blockade of NMDA receptors induces trafficking of NR2B subunits out of synaptic membranes, spines, and terminals. This is in sharp contrast to a previous observation that NR2A subunits move into spines and axon terminals following in vivo blockade with D-APV. These findings point to yet unknown, NMDA receptor activitydependent mechanisms that separately regulate the localization of NR2A and NR2B subunits at synapses. Keywordsactivity-dependent; D-APV; electron microscopy; immunocytochemistry; ultrastructure; postembedding colloidal gold labelingThe N-methyl-D-aspartate (NMDA) subtype of glutamate receptor plays an important role in experience-dependent plasticity. Calcium influx through this receptor can trigger a variety of downstream biochemical reactions, contributing to plasticity (Mori and Mishina, 1995;Kind and Neumann, 2001) and excitotoxicity (Lynch and Guttmann, 2002). One of many consequences of NMDA receptor activation is altered trafficking of proteins to and from the activated synapses. For example, long-term potentiation, in which the electrophysiological response to an input is augmented, is in part produced by NMDA receptor-dependent upregulation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (see NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 May 24. Malenka and Nicoll, 1999). In vitro and fewer in vivo preparations have been used to demonstrate that NMDA receptors, too, are removed from or inserted into synaptic membrane (Rao and Craig, 1997;Liao et al., 1999;Quinlan et al., 1999;Heynen et al., 2000;Barria and Malinow, 2002;Grosshans et al., 2002;Tovar and Westbrook, 2002). However, since nearly all of these studies have used neonatal tissues, whether or not such dynamic properties of NMDA receptor subunits persist at mature synapses, in vivo, is a topic that remains relatively unexplored.Among the NMDA receptor subunits, the NR1 is necessary for NMD...

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Section: Discussion Nr2b Subunits Occur Both Pre-and Post-synapticallymentioning

confidence: 71%

In vivo blockade of N-methyl-d-aspartate receptors induces rapid trafficking of NR2B subunits away from synapses and out of spines and terminals in adult cortex

Fujisawa

Aoki

2003

Neuroscience

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“…These results suggest the lack of AP-3 did not alter the rate of fusion pore opening or the number of postsynaptic receptors at excitatory synapses onto CA3 pyramidal cells. In addition, the higher mEPSC frequency in mocha cultures was not affected by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (A.S. and J.-C.P., unpublished observations), suggesting it did not reflect a greater activation of presynaptic NMDA receptors (14,15) because of the lack of Zn release from MF terminals in mocha mice (16,17). After 72-h incubation with TeNT, mEPSC frequency in control cultures was reduced by Ϸ84% (to 0.27 Ϯ 0.04 Hz, n ϭ 9; Fig.…”

Section: Increased Basal Release In Mocha and Brefeldin A (Bfa)-treatmentioning

confidence: 96%

Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses

Scheuber

Rudge

Danglot

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

120

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Synaptic vesicle (SV) exocytosis mediating neurotransmitter release occurs spontaneously at low intraterminal calcium concentrations and is stimulated by a rise in intracellular calcium. Exocytosis is compensated for by the reformation of vesicles at plasma membrane and endosomes. Although the adaptor complex AP-3 was proposed to be involved in the formation of SVs from endosomes, whether its function has an indirect effect on exocytosis remains unknown. Using mocha mice, which are deficient in functional AP-3, we identify an AP-3-dependent tetanus neurotoxin-resistant asynchronous release that can be evoked at hippocampal mossy fiber (MF) synapses. Presynaptic targeting of the tetanus neurotoxin-resistant vesicle soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) is lost in mocha hippocampal MF terminals, whereas the localization of synaptobrevin 2 is unaffected. In addition, quantal release in mocha cultures is more frequent and more sensitive to sucrose. We conclude that lack of AP-3 results in more constitutive secretion and loss of an asynchronous evoked release component, suggesting an important function of AP-3 in regulating SV exocytosis at MF terminals.

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“…AMPA-EPSCs were isolated by holding the postsynaptic cell at Ϫ90 mV to block voltage-dependent postsynaptic NMDARs. In addition, postsynaptic NMDARs were blocked pharmacologically in most experiments by loading the postsynaptic cell internally with the NMDA channel blocker (ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801; 1 mM) via the recording pipette (Berretta and Jones, 1996;Woodhall et al, 2001;Humeau et al, 2003;Mameli et al, 2005;Samson and Pare, 2005;V. A. Bender et al, 2006;Corlew et al, 2007), which selectively blocks postsynaptic NMDA currents without affecting NMDA currents in neighboring cells (V. A. .…”

Section: Whole-cell Recordingmentioning

confidence: 99%

“…Of the four types of NR2 subunits, cortical neurons preferentially express NR2A and/or NR2B (Monyer et al, 1994). In cortex, postsynaptic NMDARs undergo an early postnatal developmental switch from NR2B-containing to NR2A-containing receptors (Monyer et al, 1994;Flint et al, 1997;Kew et al, 1998;Stocca and Vicini, 1998;Tovar and Westbrook, 1999;Liu et al, 2004), whereas PreNMDARs are thought to preferentially retain NR2B subunits (Woodhall et al, 2001;Sjöström et al, 2003;Yang et al, 2006). To determine the subunit composition of PreNMDARs at L4 -L2/3 synapses, we applied the antagonist ifenprodil, which blocks NR2B-containing NMDARs (Williams, 1993).…”

Section: Prenmdars Contain Nr2b Subunitsmentioning

confidence: 99%

“…Presynaptic NMDARs (PreNMDARs) have been detected physiologically at many cortical synapses, including synapses onto layer 2 (L2) and L5 cells in entorhinal cortex (Berretta and Jones, 1996;Woodhall et al, 2001;Yang et al, 2006), synapses between L5 pyramidal cells in visual cortex (Sjöström et al, 2003), ascending inputs onto L2/3 pyramidal cells (presumptive L4 -L2/3 synapses) in somatosensory cortex (S1) (V. A. , and synapses onto L2/3, L4, and L5 cells in visual cortex (Corlew et al, 2007). Cortical PreNMDARs modulate transmitter release and long-term synaptic depression (LTD) (Sjöström et al, 2003;V.…”

Section: Introductionmentioning

confidence: 99%

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Synapse-Specific Expression of Functional Presynaptic NMDA Receptors in Rat Somatosensory Cortex

Brasier¹,

Feldman²

2008

J. Neurosci.

119

138

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Presynaptic NMDA receptors (NMDARs) modulate release and plasticity at many glutamatergic synapses, but the specificity of their expression across synapse classes has not been examined. We found that non-postsynaptic, likely presynaptic NR2B-containing NMDARs enhanced AMPA receptor-mediated synaptic transmission at layer 4 (L4) to L2/3 (L4 -L2/3) synapses in juvenile rat barrel cortex. This modulation was apparent at room temperature when presynaptic NMDARs were activated by elevation of extracellular glutamate or application of exogenous NMDAR agonists. At near physiological temperatures, modulation of transmission by presynaptic NMDARs occurred naturally, without the need for external activation. Blockade of presynaptic NMDARs depressed unitary and extracellularly evoked EPSCs at L4 -L2/3 synapses, accompanied by increases in paired-pulse ratio and coefficient of variation, indicative of a decrease in presynaptic release probability. NMDAR agonists increased the frequency of miniature EPSCs in L2/3 neurons, without altering their amplitude or kinetics. Focal application of NMDAR antagonist revealed that the NMDARs that modulate L4 -L2/3 transmission are located in L2/3, not L4, consistent with localization on terminals or axons of L4 -L2/3 synapses, rather than on the somatodendritic compartment of presynaptic L4 neurons. In contrast, presynaptic NMDARs did not modulate L4 -L4 synapses, which originate from the same presynaptic neurons as L4 -L2/3 synapses, or cross-columnar L2/3-L2/3 horizontal projections, which synapse onto the same postsynaptic target neurons. Thus, presynaptic NMDARs selectively modulate L4 -L2/3 synapses, relative to other synapses made by the same neurons. Existence of these receptors may support specialized processing or plasticity by L4 -L2/3 synapses.

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NR2B-Containing NMDA Autoreceptors at Synapses on Entorhinal Cortical Neurons

Cited by 120 publications

References 47 publications

In vivo blockade of N-methyl-d-aspartate receptors induces rapid trafficking of NR2B subunits away from synapses and out of spines and terminals in adult cortex

In vivo blockade of N-methyl-d-aspartate receptors induces rapid trafficking of NR2B subunits away from synapses and out of spines and terminals in adult cortex

Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses

Synapse-Specific Expression of Functional Presynaptic NMDA Receptors in Rat Somatosensory Cortex

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