Roles of Presynaptic NMDA Receptors in Neurotransmission and Plasticity

Banerjee, Abhishek; Larsen, Rylan S.; Philpot, Benjamin D.; Paulsen, Ole

doi:10.1016/j.tins.2015.11.001

Cited by 106 publications

(101 citation statements)

References 108 publications

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“…These results are supported by the findings that functional CXCR4 and NMDARs are expressed at presynaptic terminals (Larsen et al, 2011; Petralia, 2012; Reaux-Le Goazigo et al, 2012; Banerjee et al, 2016). On the other hand, gp120 was also found to potentiate glutamate-induced increase of intracellular Ca 2+ levels and to enhance extra-synaptic NR2BR-mediated EPSCs, indicating that gp120 acts on postsynaptic NMDARs as well.…”

Section: Discussionsupporting

confidence: 69%

HIV-1 Glycoprotein 120 Enhancement of N-Methyl-D-Aspartate NMDA Receptor-Mediated Excitatory Postsynaptic Currents: Implications for HIV-1-Associated Neural Injury

Zhou

Liu

Xiong

2016

J Neuroimmune Pharmacol

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It is widely accepted that human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120) plays an important role in HIV-1-induced neural injury and pathogenesis of HIV-1-associated dementia (HAND). Multiple pathways have been proposed for gp120-induced neurotoxicity, amongst is the activation of N-Methyl-D-Aspartate receptors (NMDARs). It has been shown that gp120 causes neuronal injury or death and gp120 transgenic mice exhibit neurological similarity to that of HAND, all of which can be blocked or attenuated by NMDAR antagonists. Several lines of evidence indicate the subtype and location of activated NMDARs are key determinants of the nature of NMDAR physiology. To examine the subtype and the location of NMDARs affected by gp120, we studied gp120 on subtype NMDAR-mediated EPSCs in the CA1 region of rat hippocampal slices through “blind” whole-cell patch recordings. Our results showed bath application of gp120 increased both NR2A- and NR2B-mediated EPSCs possibly via a presynaptic mechanism, with much stronger effect on NR2B-mediated EPSCs. In contrast, gp120 failed on enhancing AMPA receptor-mediated EPSCs. Ca2+ imaging studies revealed that gp120 potentiated glutamate-induced increase of intracellular Ca2+ concentration in rat hippocampal neuronal cultures which were blocked by a NMDAR antagonist, but not by an AMPA receptor antagonist, indicating gp120 induce Ca2+ influx through NMDARs. Further investigation demonstrated that gp120 increased the EPSCs mediated by extrasynaptic NR2BRs. Taken together, these results demonstrate that gp120 interacts with both NR2A and NR2B subtypes of NMDARs with a predominant action on the extrasynaptic NR2B, which may implicate a role NR2B may play in HIV-1-associated neuropathology.

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Section: Discussionsupporting

confidence: 69%

HIV-1 Glycoprotein 120 Enhancement of N-Methyl-D-Aspartate NMDA Receptor-Mediated Excitatory Postsynaptic Currents: Implications for HIV-1-Associated Neural Injury

Zhou

Liu

Xiong

2016

J Neuroimmune Pharmacol

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“…Several groups have specifically noted that the effects of nicotinic receptor activation on transmitter release are not direct, but mediated indirectly via the release of glutamate and the activation of NMDA receptors (Schilstrom et al ,b). Many of the NMDA receptors on nerve terminals are blocked by kynurenic acid including those which can release acetylcholine (Bouvier et al , ; Banerjee et al ) and other transmitters including glutamate (Ransom and Deschenes, ; Fink et al, ; Krebs et al, ; Overton and Clark, ; Garcia‐Munoz et al, ).…”

Section: Interpreting Resultsmentioning

confidence: 99%

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

Stone

2019

Journal of Neurochemistry

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As a major metabolite of kynurenine in the oxidative metabolism of tryptophan, kynurenic acid is of considerable biological and clinical importance as an endogenous antagonist of glutamate in the central nervous system. It is most active as an antagonist at receptors sensitive to N‐methyl‐D‐aspartate (NMDA) which regulate neuronal excitability and plasticity, brain development and behaviour. It is also thought to play a causative role in hypo‐glutamatergic conditions such as schizophrenia, and a protective role in several neurodegenerative disorders, notably Huntington’s disease. An additional hypothesis, that kynurenic acid could block nicotinic receptors for acetylcholine in the central nervous system has been proposed as an alternative mechanism of action of kynurenate. However, the evidence for this alternative mechanism is highly controversial, partly because at least eight earlier studies concluded that kynurenic acid blocked NMDA receptors but not nicotinic receptors and five subsequent, independent studies designed to repeat the results have failed to do so. Many studies considered to support the alternative ‘nicotinic’ hypothesis have been based on the use of analogs of kynurenate such as 7‐chloro‐kynurenic acid, or putatively nicotinic modulators such as galantamine, but a detailed analysis of the pharmacology of these compounds suggests that the results have often been misinterpreted, especially since the pharmacology of galantamine itself has been disputed. This review examines the evidence in detail, with the conclusion that there is no confirmed, reliable evidence for an antagonist activity of kynurenic acid at nicotinic receptors. Therefore, since there is overwhelming evidence for kynurenate acting at ionotropic glutamate receptors, especially NMDAR glutamate and glycine sites, with some activity at GPR35 sites and Aryl Hydrocarbon Receptors, results with kynurenic acid should be interpreted only in terms of these confirmed sites of action.

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“…The mechanism for this is not immediately clear; while it could represent a simple reduction in overall network excitability due to the removal of an excitatory postsynaptic current, it is also possible that the effect of blockade of presynaptic NMDA receptors could be involved. Presynaptic NMDA receptor activation enhances neurotransmitter release (Banerjee et al., 2016). Therefore, antagonism at these receptors may lead to a reduction in neurotransmitter release, as compared to that in control conditions; this could conceivably reduce Up state incidence, essentially by further reducing network excitation.…”

Section: Discussionmentioning

confidence: 99%

Distinct mechanisms of Up state maintenance in the medial entorhinal cortex and neocortex

et al. 2017

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The medial entorhinal cortex (mEC) is a key structure which controls the communication between the hippocampus and the neocortex. During slow-wave sleep, it stands out from other cortical regions by exhibiting persistent activity that outlasts neocortical Up states, decoupling the entorhinal cortex-hippocampal interaction from the neocortex. Here, we compared the mechanisms involved in the maintenance of the Up state in the barrel cortex (BC) and mEC using whole cell recordings in acute mouse brain slices. Bath application of an NMDA receptor antagonist abolished Up states in the BC, and reduced the incidence but not the duration of Up states in the mEC. Conversely, blockade of kainate receptors decreased Up state duration in the mEC, but not in the BC. Voltage clamp recordings demonstrated the presence of a non-NMDA glutamate receptor-mediated slow excitatory postsynaptic current, sensitive to the selective kainate receptor antagonist UBP-302, in layer III neurons of the mEC, which was not observed in the BC. Moreover, we found that kainate receptor-mediated currents assist in recovery back to the Up state membrane potential following a current-induced hyperpolarisation of individual cells in the mEC. Finally, we were able to generate Up state activity in a network model of exponential integrate-and-fire neurons only supported by AMPA and kainate receptor-mediated currents. We propose that synaptic kainate receptors are responsible for the unique properties of mEC Up states.

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Roles of Presynaptic NMDA Receptors in Neurotransmission and Plasticity

Cited by 106 publications

References 108 publications

HIV-1 Glycoprotein 120 Enhancement of N-Methyl-D-Aspartate NMDA Receptor-Mediated Excitatory Postsynaptic Currents: Implications for HIV-1-Associated Neural Injury

HIV-1 Glycoprotein 120 Enhancement of N-Methyl-D-Aspartate NMDA Receptor-Mediated Excitatory Postsynaptic Currents: Implications for HIV-1-Associated Neural Injury

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

Distinct mechanisms of Up state maintenance in the medial entorhinal cortex and neocortex

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