Tonic facilitation of glutamate release by presynaptic N-methyl-d-aspartate autoreceptors in the entorhinal cortex

doi:10.1016/0306-4522(96)00301-6

Neuroscience

Volume 75, Issue 2, 25 October 1996, Pages 339-344

https://doi.org/10.1016/0306-4522(96)00301-6 Get rights and content

Abstract

N-Methyl-d-aspartate receptors are fundamental for neuronal plasticity and development in the CNS.3, 21Most studies have examined postsynaptic roles of this receptor, but there are also indications for a presynaptic location and function.6, 18, 23Here, we provide electrophysiological evidence for the existence of presynaptic N-methyl-d-aspartate receptors which can tonically facilitate glutamate release in the CNS. The N-methyl-d-aspartate receptor antagonist 2-amino-5-phosphonopentanoate reduced the frequency, but not amplitude, of glutamate-mediated spontaneous excitatory postsynaptic currents in layer II neurons of the rat. When extracellular calcium was replaced with strontium, 2-amino-5-phosphonopentanoate reduced the “tail” of spontaneous excitatory postsynaptic currents that followed an evoked excitatory postsynaptic current. Finally, there was a tendency for paired-pulse facilitation of excitatory postsynaptic currents evoked at short (50 ms) intervals and for postsynaptic N-methyl-d-aspartate receptors blocked to be reduced by 2-amino-5-phosphonopentanoate, although this did not reach significance.

These data strongly support the presence of presynaptic N-methyl-d-aspartate autoreceptors which may facilitate glutamate release in layer II of the entorhinal cortex.

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Acknowledgements

We thank the Wellcome Trust and Royal Society for financial support, P. Vincent for the software for the analysis program and C. Stoub for the Kolmogorov–Smirnov test.

References (27)

M.G Blanton et al.
Whole-cell recording from neurones in slices of reptilian and mammalian cerebral cortex
J. Neurosci. Meth.
(1989)
G Bustos et al.
Regulation of excitatory amino acid release by N-methyl-d-aspartate receptors in rat striatum: in vivo microdialysis studies
Brain Res.
(1992)
K Fink et al.
Presynaptic NMDA receptors stimulate noradrenaline release in the cerebral cortex
Eur. J. Pharmac.
(1990)
G Hess et al.
Quantal analysis of paired-pulse facilitation in guinea pig hippocampal slices
Neurosci. Lett.
(1987)
R.S.G Jones
Entorhinal–hippocampal connections: a speculative view of their functions
Trends Neurosci.
(1993)
B Moghaddam et al.
Effect of l-glutamate on the release of striatal dopamine: in vivo dialysis and electrochemical studies
Brain Res.
(1990)
M Vignes et al.
Pharmacological evidence for an involvement of group II and group III mGluRs in the presynaptic regulation of excitatory synaptic responses in the CA1 region of rat hippocampal slices
Neuropharmacology
(1995)
A Baskys et al.
Agonists of metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus
J. Physiol., Lond.
(1991)
N Berretta et al.
A comparison of spontaneous EPSCs in layer II and layer IV–V neurones of the rat entorhinal cortex in vitro
J. Neurophysiol.
(1996)
T.V.P Bliss et al.
A synaptic model of memory: long-term potentiation in the hippocampus
Nature
(1993)

H Braak et al.

Neuropathological staging of Alzheimer-related changes

Acta neuropath.

(1991)

R Chittajallu et al.

Regulation of glutamate release by presynaptic kainate receptors in the hippocampus

Nature

(1996)

C.H Desai et al.

Multiple metabotropic glutamate receptors regulate hippocampal function

Synapse

(1992)

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Multiple roles of GluN2D-containing NMDA receptors in short-term potentiation and long-term potentiation in mouse hippocampal slices
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The GluN2 subunits of N-methyl-d-aspartate receptors (NMDARs) are key drivers of synaptic plasticity in the brain, where the particular GluN2 composition endows the NMDAR complex with distinct pharmacological and physiological properties. Compared to GluN2A and GluN2B subunits, far less is known about the role of the GluN2D subunit in synaptic plasticity. In this study, we have used a GluN2C/2D selective competitive antagonist, UBP145, in combination with a GluN2D global knockout (GluN2D KO) mouse line to study the contribution of GluN2D-containing NMDARs to short-term potentiation (STP) and long-term potentiation (LTP) in the CA1 region of mouse hippocampal slices. We made several distinct observations: First, GluN2D KO mice have higher levels of LTP compared to wild-type (WT) mice, an effect that was occluded by blockade of GABA receptor-mediated inhibition or by using a strong LTP induction protocol. Second, UBP145 partially inhibited LTP in WT but not GluN2D KO mice. Third, UBP145 inhibited a component of STP, termed STP2, in WT but not GluN2D KO mice. Taken together, these findings suggest an involvement for GluN2D-containing NMDARs in both STP and LTP in mouse hippocampus.
This article is part of the Neuropharmacology Special Issue on ‘Glutamate Receptors – NMDA receptors’.
NMDA receptors and synaptic plasticity in the anterior cingulate cortex
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The anterior cingulate cortex (ACC) plays an important role in pain modulation, and pain-related emotional disorders. In the ACC, two major forms of long-term potentiation (LTP) coexist in excitatory synapses and lay the basis of chronic pain and pain-related emotional disorders. The induction of postsynaptic LTP is dependent on the activation of postsynaptic NMDA receptors (NMDARs), while the presynaptic LTP is NMDAR-independent. Long-term depression (LTD) can also be divided into two types according to the degree of sensitivity to the inhibition of NMDARs. NMDAR heteromers containing GluN2A and GluN2B act as key molecules in both the NMDAR-dependent postsynaptic LTP and LTD. Additionally, NMDARs also exist in presynaptic terminals and modulate the evoked and spontaneous transmitter release. From a translational point of view, inhibiting subtypes of NMDARs and/or downstream signaling proteins may provide potential drug targets for chronic pain and its related emotional disorders.
This article is part of the special Issue on ‘Glutamate Receptors –NMDA receptors’.
Relocation of an Extrasynaptic GABA<inf>A</inf> Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory
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Citation Excerpt :
To confirm that the synaptic redistribution of α5-GABAR is specific to the monosynaptic connection, we included the NMDAR antagonist MK-801 (1 mM) in the patch pipette. MK-801 is membrane-impermeant and can block NMDARs from the intracellular side (Berretta and Jones, 1996). Additionally, we voltage clamped the membrane potential to −70 mV to suppress LTP induction (Malinow and Tsien, 1990) and waited >10 min before TBS to promote washout of constituents necessary for LTP induction.
The excitatory synapse between hippocampal CA3 and CA1 pyramidal neurons exhibits long-term potentiation (LTP), a positive feedback process implicated in learning and memory in which postsynaptic depolarization strengthens synapses, promoting further depolarization. Without mechanisms for interrupting positive feedback, excitatory synapses could strengthen inexorably, corrupting memory storage. Here, we reveal a hidden form of inhibitory synaptic plasticity that prevents accumulation of excitatory LTP. We developed a knockin mouse that allows optical control of endogenous α5-subunit-containing γ-aminobutyric acid (GABA)_A receptors (α5-GABARs). Induction of excitatory LTP relocates α5-GABARs, which are ordinarily extrasynaptic, to inhibitory synapses, quashing further NMDA receptor activation necessary for inducing more excitatory LTP. Blockade of α5-GABARs accelerates reversal learning, a behavioral test for cognitive flexibility dependent on repeated LTP. Hence, inhibitory synaptic plasticity occurs in parallel with excitatory synaptic plasticity, with the ensuing interruption of the positive feedback cycle of LTP serving as a possible critical early step in preserving memory.
Propofol facilitates climbing fiber-Purkinje cell synaptic transmission via NMDA receptor in vitro in mice
2020, European Journal of Pharmacology
Propofol is generally used for the induction and maintenance of anesthesia in clinical procedures via activation of γ -aminobutyric acid A (GABA_A) receptors. When administered at the clinical dose, propofol use is associated with movement disorders, including dystonia and ataxia, suggesting that propofol administration impacts the function of cerebellar neuronal circuitry. In this study, we investigated the effect of propofol on climbing fiber (CF)-Purkinje cell (PC) synaptic transmission in mouse cerebellar slices in the absence of GABAergic inhibition using a whole-cell recording technique and pharmacological methods. Our results showed that bath application of propofol enhanced CF-PC synaptic transmission, which was demonstrated by an increased amplitude and area under the curve (AUC) of the excitatory postsynaptic currents (EPSCs) accompanied by a decrease in the paired-pulse ratio (PPR). The propofol-induced increase in the amplitude of P1 was concentration-dependent with a half effective concentration (EC₅₀) of 20.9 μM. The propofol-induced increases in the amplitude and AUC of CF-PC EPSCs were abolished by an N-Methyl-D-aspartate (NMDA) receptor blocker. Furthermore, the application of NMDA enhanced CF-PC EPSCs and overwhelmed the effect of propofol on CF-PC EPSCs. Moreover, intracellular blockade of NMDA receptors attenuated the propofol-induced enhancement of CF-PC synaptic transmission but strengthened the propofol-induced change in the PPR. These results indicate that propofol enhances CF-PC synaptic transmission by activation of NMDA receptors in the mouse cerebellar cortex, suggesting that propofol administration might be involved in propofol-induced dysfunction of the cerebellum via NMDA receptors.
NMDA receptors sustain but do not initiate neuronal depolarization in spreading depolarization
2020, Neurobiology of Disease
Spreading depolarization (SD) represents a neurological process characterized by a massive, self-sustaining wave of brain cell depolarization. Understanding its mechanism is important for treating ischemic or hemorrhagic stroke and migraine with aura. Many believed that ion fluxes through NMDA receptors (NMDARs) are responsible for neuronal transmembrane currents of SD. However, the explicit role of NMDARs remains ambiguous. This is in part due to the limitation of traditional pharmacological approaches in resolving the contribution of NMDARs in different intercellular and intracellular processes of SD. Here, we applied single-cell blockade and genetic deletion methods to remove functional NMDARs from individual hippocampal CA1 neurons in order to examine the role of NMDARs in the depolarization mechanism without affecting the propagation of SD. We analyzed neuronal membrane potential changes to demonstrate that NMDARs are not required for initiating the depolarization. Consistently, neuronal input resistance (R_N) revealed a sharp decline at the start of SD, which was unaffected by blocking NMDARs. Instead, the recovery of both membrane potential and R_N during the late phase of SD was facilitated by inhibition of NMDARs, indicating that NMDARs are responsible for sustaining the depolarization. Our results strongly indicate that NMDAR activation is not a determinant of the initiation of depolarization but is important for sustaining transmembrane ion fluxes during SD.
Incomplete block of NMDA receptors by intracellular MK-801
2018, Neuropharmacology
NMDA receptors (NMDARs) are essential components in glutamatergic synaptic signaling. The NMDAR antagonist MK-801 has been a valuable pharmacological tool in evaluating NMDAR function because it binds with high affinity to the NMDAR ion channel pore and is non-competitive with ligand binding. MK-801 has also been used to selectively inhibit NMDAR current in only the cell being recorded by including the drug in the intracellular recording solution. Here, we report that intracellular MK-801 (iMK-801) only partially inhibits synaptic NMDAR currents at +40 mV at both cortical layer 4 to layer 2/3 and hippocampal Schaffer collateral to CA1 synapses. Furthermore, iMK-801 incompletely inhibits heterologously expressed NMDAR currents at −60 mV, consistent with a model of iMK-801 having a very slow binding rate and consequently ∼30,000 times lower affinity than MK-801 applied to the extracellular side of the receptor. While iMK-801 can be used as a qualitative tool to study reduced postsynaptic NMDAR function, it cannot be assumed to completely block NMDARs at concentrations typically used in experiments.

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¹: Present address: SISSA—ISAS International School for Advanced Studies, Via Beirut 2/4, 34014, Trieste, Italy.

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Neuroscience

Abstract

Section snippets

Unlinked list

Acknowledgements

References (27)

Whole-cell recording from neurones in slices of reptilian and mammalian cerebral cortex

J. Neurosci. Meth.

Regulation of excitatory amino acid release by N-methyl-d-aspartate receptors in rat striatum: in vivo microdialysis studies

Brain Res.

Presynaptic NMDA receptors stimulate noradrenaline release in the cerebral cortex

Eur. J. Pharmac.

Quantal analysis of paired-pulse facilitation in guinea pig hippocampal slices

Neurosci. Lett.

Entorhinal–hippocampal connections: a speculative view of their functions

Trends Neurosci.

Effect of l-glutamate on the release of striatal dopamine: in vivo dialysis and electrochemical studies

Brain Res.

Pharmacological evidence for an involvement of group II and group III mGluRs in the presynaptic regulation of excitatory synaptic responses in the CA1 region of rat hippocampal slices

Neuropharmacology

Agonists of metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus

J. Physiol., Lond.

A comparison of spontaneous EPSCs in layer II and layer IV–V neurones of the rat entorhinal cortex in vitro

J. Neurophysiol.

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

Neuropathological staging of Alzheimer-related changes

Acta neuropath.

Regulation of glutamate release by presynaptic kainate receptors in the hippocampus

Nature

Multiple metabotropic glutamate receptors regulate hippocampal function

Synapse

Cited by (214)

Multiple roles of GluN2D-containing NMDA receptors in short-term potentiation and long-term potentiation in mouse hippocampal slices

NMDA receptors and synaptic plasticity in the anterior cingulate cortex

Relocation of an Extrasynaptic GABA<inf>A</inf> Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory

Propofol facilitates climbing fiber-Purkinje cell synaptic transmission via NMDA receptor in vitro in mice

NMDA receptors sustain but do not initiate neuronal depolarization in spreading depolarization

Incomplete block of NMDA receptors by intracellular MK-801

Letter to NeuroscienceTonic facilitation of glutamate release by presynaptic N-methyl-d-aspartate autoreceptors in the entorhinal cortex

Abstract

Section snippets

Unlinked list

Acknowledgements

J. Neurosci. Meth.

Brain Res.

Eur. J. Pharmac.

Neurosci. Lett.

Trends Neurosci.

Brain Res.

Neuropharmacology

Agonists of metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus

J. Physiol., Lond.

A comparison of spontaneous EPSCs in layer II and layer IV–V neurones of the rat entorhinal cortex in vitro

J. Neurophysiol.

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

Neuropathological staging of Alzheimer-related changes

Acta neuropath.

Regulation of glutamate release by presynaptic kainate receptors in the hippocampus

Nature

Multiple metabotropic glutamate receptors regulate hippocampal function

Synapse

Letter to Neuroscience
Tonic facilitation of glutamate release by presynaptic N-methyl-d-aspartate autoreceptors in the entorhinal cortex