My NCBISign In
Print View 

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press; 2009.

Bookshelf ID: NBK5275PMID: 21204409

Chapter 14Presynaptic NMDA Receptors

Ian C. Duguid and Trevor G. Smart.

14.1INTRODUCTION

Go to:

Presynaptic receptors, by virtue of their locations, are ideally suited to influence the efficacy of synaptic transmission by affecting neurotransmitter release [58]. In the nervous system, action potential invasion of presynaptic terminals results in a characteristic series of events: initial Ca2+ entry, followed by the activation of presynaptic vesicular release machinery, vesicular fusion, and the release of neurotransmitter into the synaptic cleft [103,105]. The efficacy of synaptic transmission is thus governed by the probability of neurotransmitter release, the amount of transmitter released from the presynaptic terminal, the type and number of postsynaptic neurotransmitter receptors, and their response to the released transmitter.

Short- and long-term activity-dependent modulation of the efficacy of a synapse can proceed via a multitude of signaling mechanisms that impact on either the presynaptic release or the receptors that mediate postsynaptic responses [13,66,102]. Such modulatory mechanisms will be crucial for regulating the flow of information throughout the nervous system and have been implicated in many neural processes including learning and memory, vision, motor control, and neuroprotection.

Modulation of transmitter release at a synapse was first demonstrated in the classical studies of Dudel and Kuffler [30] and Eccles [33] who identified that presynaptic GABA receptors inhibited transmitter release from crustacean motor neuron terminals and vertebrate sensory neuron terminals in the spinal cord, respectively. Since then, the modulation of transmitter release by presynaptic receptors is an accepted signaling pathway, and although the focus of attention initially fell on metabotropic G-protein coupled receptors [52,94], it soon became clear that numerous populations of presynaptic ionotropic receptors are equally important [53,58,67].

One receptor that has not featured prominently as a presynaptic regulator of transmitter release is the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptor. It was first proposed to have a presynaptic locus of expression after it was found that exogenously applied NMDA facilitated the release of tritiated neurotransmitter from synaptosomes prepared from noradrenergic terminals in the hippocampus [86], cerebral cortex [37], and from dopaminergic terminals in the striatum [50,56,112]. Because of the nature of the preparations, these early studies failed to identify the exact loci of NMDA receptor (NMDAR) subunit expression.

Further evidence for presynaptic NMDARs came from the pioneering work of Liu and colleagues [62] who identified NR1 subunit immunoreactivity in both the dorsal and ventral horns of the rat spinal cord, specifically on axon terminals and very near the active zone, indicating a direct role in the regulation of transmitter release. Similarly, immunoreactivity for NR1 and NR2 was found on presynaptic boutons in rat cerebellar cortex [82,83] and at mossy fiber CA synapses in monkey hippocampus [98]. These early findings provided the necessary impetus to find a more widespread role for presynaptic NMDARs in the regulation of neuronal signaling in the CNS.

In this chapter, we discuss recent advances in our understanding of presynaptic NMDARs as important modulators of synaptic transmission. We consider the potential sources of glutamate for NMDAR activation; the downstream signaling mechanisms that ensue; and the differing forms of synaptic plasticity mediated by presynaptic NMDARs that undoubtedly help sculpt information processing in the brain.

14.2CRITERIA FOR DEFINING PRESYNAPTIC RECEPTORS

Go to:

Ideally, before attempting to classify a receptor as having a putative presynaptic location and roles in modulating neurotransmitter release, several criteria should be satisfied:

  1. Immunohistochemical or electron microscopic (EM) evidence of a presynaptic location of receptor subunits at a given synapse.

  2. Presence of the modulatory transmitter at or adjacent to a synapse.

  3. Exogenous application of the transmitter should mimic physiological activation of the receptor.

  4. Selective receptor antagonists should block presynaptic receptor activation.

  5. Downstream signaling cascades leading to altered transmitter release should be identified in the presynaptic axon terminals.

  6. Activation of the presynaptic receptor should affect the frequency of miniature synaptic currents in preference to their amplitudes.

  7. The paired-pulse ratio (PPRs) of the amplitudes of two consecutively evoked synaptic currents should be increased or decreased by presynaptic receptor activation. Caution is required when using the PPR as a sole indicator of presynaptic receptor activation as postsynaptic mechanisms can contribute to a change in PPR [55].

  8. Measurement of a change in the coefficient of variation (CV) of evoked synaptic current amplitudes.

Frequent use is made of comparing the CV with the mean amplitude (m) of evoked synaptic currents to deduce whether variations in synaptic efficacy have their origins at presynaptic or postsynaptic locations. Generally, proportionate changes in CV−2 and m indicate presynaptic modulation of transmitter release, whereas changes to m without alteration to CV−2 indicate modulation of postsynaptic receptors.

14.3LOCATIONS OF NMDA RECEPTORS AT SYNAPSES

Go to:

Although it is widely known that NMDARs are located at the postsynaptic densities of excitatory synapses [27,78], where they mediate the slow excitatory postsynaptic potential, their locations on presynaptic axon terminals, has been more contentious. Early trafficking studies revealed that NMDARs are potentially mobile by radiola-belling with the antagonist CPP. They were shown to move bidirectionally along the vagus nerve and were restricted by its ligation [23].

At the light and electron microscopy level, positive immunoreactivity has been observed for NMDAR subunits on a wide variety of asymmetrical synapses throughout the mammalian brain, including the dorsal and ventral horns of the spinal cord [62], neocortex [29], hippocampus [82,98], cerebellar cortex [82], visual cortex [4], anterior cingulate cortex [111], nucleus accumbens [42], amygdala [35], and retina [113]. Immunoreactivity for NR2B subunits has also been reported on axonal growth cones isolated from embryonic day 18 (E18) brains [45]. These reports illustrate the potentially widespread distribution of presynaptic NMDARs that may affect excitatory synaptic transmission in the mammalian CNS.

Immunoreactivity for NMDAR subunits can also be found at symmetrical synapses on subpopulations of GABAergic inhibitory boutons in the bed nucleus of the stria terminalis, cerebellar cortex, paraventricular hypothalamic nucleus, neocortex, and arcuate nucleus [29,32,81]. Rich plexuses of NR1-immunoreactive terminal-like varicosities are present in many nuclei in the basal forebrain, midline thalamus, and peri-ventricular hypothalamus [81]. Surprisingly, very few NR1 labeled fibers are apparent in the midbrain, brainstem, and at some cortical levels, suggesting the distribution of presynaptic NMDAR subunits is seemingly confined to brain structures involved in controlling autonomic, neuroendocrine, and limbic functions.

Many earlier observations reported the presence of one type of NMDAR subunit, but this does not constitute proof that functional receptors are present because they are formed only after hetero-oligomerization [73]. Although it is possible to detect immunoreactivity for multiple NMDAR subunits on the same axon terminals (NR1 and NR2A–D are all expressed on axon terminals of interneurons that synapse with Purkinje cells in the cerebellum [32]), this also does not prove that functional NMDAR channels are present. Thus, positive immunoreactivity per se does not confirm the presence of functional presynaptic receptors, which can be assessed only via electro-physiological approaches (see criteria).

14.4PHARMACOLOGY OF PRESYNAPTIC NMDA RECEPTORS

Go to:

With regard to the NMDAR isoforms present on presynaptic terminals, immunocytochemical studies can only suggest potential subunit assemblies, unless, of course, subunit expression is limited to the NR1 subunit and a single NR2 isoform. We know that the minimum requirement for NMDAR cell surface expression is for a single NR1 subunit and at least one NR2 subunit isoform. While the type of NR2 subunit incorporated influences the pharmacological and physiological properties of NMDAR [26,72,80], very few ligands can definitively distinguish among NMDAR isoforms.

Our selection of certain studies as exemplars highlights the usefulness of selective ligands and the potential problems of interpreting the data. Ifenprodil, an NR2B selective ligand [116], was used to deduce that NR1 and NR2B receptors are present on axon terminals in the visual cortex [99] and entorhinal cortex [117]. By contrast, in the hippocampus, receptors comprised of NR1 and NR2A were thought to reside on Schaffer collateral terminals, promoting axon excitability and enhancing glutamate release. The presynaptic expression of NR2A was deduced because the increase in axon excitability by applied NMDA was inhibited not by ifenprodil, but by NVP-AAM077 [104]—an NR2A, selective, antagonist [10,63].

Caution is required when using selective NMDAR antagonists to deduce subunit compositions of presynaptic NMDARs. For example, NVP-AAM077 can inhibit receptors comprising NR1 and NR2B subunits [10]. The difference between the Ki values for NVP-AAM077 inhibiting the activation of NR1/NR2A and NR1/NR2B receptors is only 10-fold [80]—the absolute minimum for any ligand to show reasonably useful selectivity between two receptor isoforms. To complicate matters, NVP-AAM077 also has appreciable affinity for receptors containing the NR2C or NR2D subunit; the Kis are only 1.6- and 7-fold higher, respectively, than for NR2A subunit-containing receptors [36,80]. The closeness of the Kis for the current class of competitive antagonists at recombinant NMDARs suggests they are not well suited for distinguishing NMDAR isoforms.

An alternative approach may be utilizing ion channel blockers such as Mg2+, phencyclidine, ketamine, memantine, MK-801, and argiotoxin-636. Moreover, with the exception of argiotoxin-636, these agents are poorly selective among NMDAR isoforms [80]. The most selective is MK-801 that exhibits a 10-fold separation in Kis for NR2A or NR2B over NR2C or NR2D subunit-containing NMDARs [118]. Argiotoxin-636 is of some interest. Although it cannot distinguish NR2A and NR2B subunit-containing receptors, it will select for receptors that contain either of these over NR2C or NR2D subunit-containing receptors for which the Ki is around 50-fold higher [89].

The final class of compounds in the pharmacological armamentarium for the NMDAR constitutes the allosteric ligands that bind primarily to the N-terminal regions of the NR2 subunits. Ifenprodil, an NR2B selective antagonist, is one of the more useful compounds, exhibiting a greater than 200-fold selectivity over NR2A, 2C, and 2D subunit-containing receptors [116]. This is surpassed by CP101-606 [75] and Ro25-6981 [38] that showed 750- and 3300-fold greater selectivities, respectively, for the NR2B subunit.

Another N-terminal inhibitor that may prove more useful in distinguishing NMDAR isoforms is the divalent cation Zn2+ [100, 101]. Zinc ions are at least 100-fold more potent (based on IC50) as inhibitors at NR1/NR2A receptors compared to the next most sensitive NMDAR isoform containing NR1/NR2B subunits [79,107] and approximately 1000- and 500-fold more potent than at NR2C and NR2D subunit-containing receptors [80,88]. Although Zn2+ appears ideal for differentially detecting NR2A, and possibly NR2B subunits, it is important to note that the inhibition saturates at less than 100% at high Zn2+ concentrations [88]; thus a residual response is always present. Low concentrations of Zn2+ can also potentiate glycine receptor function and inhibit some isoforms of GABAA receptors [100].

The pharmacology of putative presynaptic NMDARs is therefore complex and our desire to achieve clarity is hampered by a lack of highly selective ligands. A further complication arises from the ability of NMDARs to not just form diheteromers but also triheteromers, possibly incorporating more than one type of NR2 subunit [22,84]. Unfortunately, the pharmacology of these triheteromers is insufficiently distinct for the current crop of ligands to be able to unequivocally distinguish their presence among native NMDARs in neurons [44]. We can also add the possibility that triheteromers may incorporate NR1, NR2, and NR3 subunits [2,28,93]. Although such a subunit combination will exert effects on single channel conductance and permeability to Ca2+, ligands with suitable selectivity are lacking. Whether the NR3A subunit is a subunit partner for presynaptic NMDARs remains to be seen.

14.5SOURCES OF GLUTAMATE

Go to:

To better understand the physiological role of presynaptic NMDARs in mammalian brains, we must first consider the sources of glutamate that may activate presynaptic NMDARs: (1) glutamate released from the same terminal on which the receptors are expressed (autoreceptor); (2) direct synaptic excitation of presynaptic boutons (axo-axonic); (3) diffusion of glutamate from an adjacent active terminal (spillover); and (4) following the activity-dependent release of glutamate from the dendrites of a postsynaptic cell (retrograde); and (5) release from surrounding glial cells (paracrine).

14.5.1Presynaptic Autoreceptors

Several neurotransmitters have been shown to modulate their own releases through relatively well-defined presynaptic autoreceptor systems [90]. However, the existence and functional role of presynaptic NMDA autoreceptors remains less well-defined and has been complicated by the presence of such receptors on the postsynaptic side of the synapse. The first evidence to suggest that NMDARs could modulate the release of glutamate appeared in the early 1990s when NMDAR antagonists were shown to reduce K+-evoked glutamate release from CA1 hippocampal neurons [71]. In addition, in vivo dialysis of NMDAR agonists resulted in a dose-dependent increase in the extracellular concentration of glutamate in the striatum, indicative of presynaptic NMDARs being located on cortico-striatal nerve endings [18].

In terms of synaptic transmission, bath application of NMDAR agonists (e.g., NMDA) and antagonists (e.g., D-APV) alters the frequency of spontaneous and miniature EPSCs in the entorhinal cortex [11,117], spinal cord [8,92], visual cortex [99], and cerebellar cortex [19,41]. This type of modulation is indicative of tonic activation of presynaptic NMDARs by, presumably, ambient glutamate. These effects persisted in the background presence of tetrodotoxin (TTX) and when postsynaptic neurons were dialyzed with MK-801, thus excluding the possibility that the effects on synaptic current frequency resulted from a change in NMDAR-dependent network activity or activation of postsynaptic NMDARs. As expected for a coincidence detector, varying the extracellular Mg2+ concentration or increasing presynaptic afferent activity enhanced the effects of presynaptic NMDAR activation. Low rates of afferent activation would cause insufficient terminal depolarization, leading to incomplete relief from Mg2+ block of NMDARs. Higher activation rates would be more effective by allowing coincident detection of extracellular glutamate [8,19, 43,92,99,117].

Interestingly, tonic facilitation of transmission in the entorhinal cortex, where NR1 and NR2B subunits are thought to be important [11,117], decreases during development. However, this is not associated with a switch in subunit expression [87,63] but instead it appears that the loss of autoreceptor function in adult animals may reflect decreases in surface expression of presynaptic NR2B subunits or a redistribution of NR2 subunit-containing receptors to a location relatively inaccessible to ambient glutamate [120]. The loss of function observed in older animals was reversed if the animals suffered chronic epileptic seizures, indicating that this pathophysiological state caused an upregulation of NR2B subunit expression, a redistribution of NMDARs to sites accessible to ambient glutamate, or a change in the composition of the existing nonredistributed NMDARs [120].

Although the data does not functionally link increased expression of presynaptic NMDA autoreceptors and epileptogenesis, it indicates a possible link between presynaptic autoreceptor function, enhanced basal glutamate release, and elevated network excitability in the entorhinal cortex. It will be of interest to see whether other pathophysiological states are capable of altering presynaptic NMDA autoreceptor activity.

Presynaptic NMDA autoreceptors may also play a role in long-term synaptic plasticity. For example, in neocortical layer 5 pyramidal neurons, a form of long-term depression (LTD) known as timing-dependent LTD (tLTD) relies on postsynaptic action potential firing preceding presynaptic afferent activity. This causes the simultaneous activation of presynaptic endocannabinoid (CB1) receptors and NMDARs [99]. The CB1 receptors detect the extent of postsynaptic activity through the retrograde release of endocannabinoids, whereas the presynaptic NMDA autoreceptors are sensors for presynaptic spiking. The initial spike acts to relieve the Mg2+ block, while subsequent spikes lead to glutamate pooling around the terminal and activation of presynaptic NMDA autoreceptors.

In a similar manner, presynaptic NMDA autoreceptors also play a role at layer 4 to layer 2/3 synapses in the somatosensory cortex during the induction of spike timing-dependent plasticity (STDP) [9]. Similar to the induction of tLTD in visual cortex, STDP also requires retrograde endocannabinoid signaling and activation of apparently presynaptic classed as (non-postsynaptic) NMDARs [9].

Presynaptic NMDARs also feature in LTD of parallel fiber inputs in the cerebellum [19,20]. In this case, a presynaptic NMDAR-mediated Ca2+ influx activates neuronal nitric oxide synthase (nNOS) to produce NO in the parallel fibers. This is thought to diffuse across the synapse to the Purkinje cell where, by activation of guanylate cyclase, cGMP is produced, resulting in the activation of cGMP-dependent protein kinase (PKG) [59]. Ultimately, this signaling pathway could result in inhibition of protein phosphatases (likely to be PP1 and PP2A) in Purkinje cells and the phosphorylation of AMPARs, possibly GluR2 at Ser-880. This will then cause their internalization and ensuing LTD [48,49]. Given the a lack of functional NMDARs on Purkinje cells [85,91], the logical explanation is that repetitive parallel fiber activation triggers autoreceptor activation of presynaptic NMDARs expressed at parallel fiber axon terminals to initiate a signaling cascade leading to LTD [19,20].

However, an alternative plausible explanation was suggested by a recent study from Shin and Linden [97]. They proposed that the NMDAR–NO cascade involved in cerebellar LTD is not localized to parallel fibers, but to interneuronal axon terminals [97]. The presynaptic NMDARs are most likely activated by glutamate spillover from the PFs, leading to NO release from interneurons that diffuses to the Purkinje cells to evoke LTD. The difficulty in deducing the correct explanation stems from a lack of detailed EM immunostaining for NMDAR subunits on nerve terminals in the cerebellum.

Although in general the data on presynaptic NMDA autoreceptor function is limited, the widespread distribution of presynaptic NMDARs on asymmetrical synapses, as indicated by electron microscopy studies (see previous section), suggests that autoreceptor regulation of synaptic transmission will be a prevalent feature of information processing throughout the mammalian CNS (Figure 14.1A).

FIGURE 14.1. (See color insert following page 212.

FIGURE 14.1

(See color insert following page 212.) Presynaptic NMDAR activation by released glutamate. (A) Presynaptic autoreceptor activation. High-frequency afferent stimulation (100 Hz) onto a layer 5 (L5) neocortical neuron enables presynaptically released glutamate (more...)

14.5.2Axo-Axonic Synapses

Axon terminals are normally considered output devices, modulated by presynaptic receptors and ion channels. Extracellular stimulation in the spinal cord results in synaptically evoked excitatory currents in the axons of reticulospinal neurons [24]. As synaptic potentials can be generated in either direction, and are sensitive to block by D-APV [24,25], they probably originate from axo-axonic synapses (Figure 14.1B) [34].

The excitatory innervation of reticulospinal axons may come from dorsal root ganglion primary afferents [14], excitatory interneurons [15,17], and other reticulospinal neurons [16]. These synaptic inputs occur at various locations along axons and the latency of the input is directly associated with the distance of the stimulation electrode from the recording electrode. Tetanic stimulation of inputs to the reticulospinal axon results in a prolonged NMDAR-dependent increase in terminal Ca2+ concentration that can last for several seconds.

The depolarization resulting from NMDAR activation is insufficient to activate voltage-activated Ca2+ channels, indicating that Ca2+ must enter solely via the activated NMDAR ion channels to enhance transmitter release [25]. The presence of axo-axonic excitatory synapses is not unique to the lamprey; they appear to exist also on afferent fibers of frog spinal cord [109]. Although there is no evidence to support a role for excitatory axo-axonic synapses in the mammalian CNS, the diverse expression of presynaptic NMDARs suggests that they could potentially play a role in modulating synaptic transmission.

14.5.3Spillover

Synaptic transmission during minimal presynaptic afferent activity is largely constrained to the postsynaptic density (PSD). This area is considered to form the boundary of a synapse. The diffusion of neurotransmitter from this boundary is largely controlled, in the case of glutamate, by the density and activity of surrounding excitatory amino acid transporters [77,106,108]. However, during periods of more intense presynaptic activity, the concentration of neurotransmitter in the cleft can rise sufficiently to saturate transporter-based mechanisms, leading to their inability to control the spatial spread of neurotransmitter to peri- and extrasynaptic sites.

The process of transmitter spillover acts to reduce synapse independence, while promoting heterosynaptic activation and synaptic crosstalk (Figure 14.1C) [57,70]. The biophysical characteristics and high affinity of NMDARs for glutamate are pivotal for “sensing” transmitter spillover from adjacent sites [26,119]. Such a role for NMDARs has been extensively studied in the cerebellum. Here repetitive stimulation of climbing fiber (CF) inputs to Purkinje cells reduces the amplitude of sIPSCs via NMDAR activation. This was explained by glutamate spillover from CF synapses, resulting in activation of presynaptic NMDARs on adjacent interneuron axon terminals/boutons [32,41]. Inhibition of glutamate uptake by TBOA, a nontransportable neuronal and glial transporter antagonist [95,96], resulted in a significant enhancement in synaptic crosstalk between excitatory and inhibitory inputs in the cerebellar cortex [46]. Therefore, glial glutamate transporters, and to a lesser extent neuronal transporters, strictly control the spatial spread of glutamate from CF synapses [3,7].

The spillover of glutamate to neighboring synapses is not restricted to CF synapses in the cerebellum; high-frequency bursts of parallel fiber (PF) activity similar to that observed in vivo [21] also produces glutamate pooling and spillover to nearby interneuron axon terminals. The resulting presynaptic NMDAR-dependent increase in inhibitory synaptic efficacy can last several ten of minutes [64].

Activation of presynaptic NMDARs on GABAergic inputs by released glutamate is not exclusive to the cerebellum. Lien and colleagues [61] showed that light-induced or theta burst stimulation of the optic nerve in the developing Xenopus retinotectal system induced LTP of glutamatergic inputs and LTD of GABAergic inputs onto the same tectal neuron. Although both forms of plasticity were blocked by D-APV, only LTP of excitatory afferents was abolished by infusing the tectal cell with MK-801. This suggests that high-frequency stimulation of excitatory afferents resulted in spillover activation of NMDARs on adjacent interneuron terminals, which were depolarized by the same theta burst stimulation. These findings provided the first evidence for the involvement of presynaptic NMDARs in coincidence detection and synaptic plasticity in vivo.

Spillover activation of presynaptic NMDARs has also been implicated in a form of associative long-term plasticity of cortical afferents in the amygdala. By coincidently stimulating converging inputs to the amygdala from the thalamus and cortex, LTP resulted, but only at the cortical afferent synapses [47]. Blocking postsynaptic NMDARs with intracellular MK-801 did not prevent LTP induction, indicating that the NMDARs required for associative LTP must have a presynaptic locus of expression in accord with the presence of NR1 subunits on presynaptic terminals in the amygdala [35]. It is conceivable that stimulation of thalamic inputs may directly activate presynaptic NMDARs on adjacent cortical axon terminals. The induction of LTP will then be restricted to those cortical synapses that are active during thalamic afferent stimulation.

14.5.4Retrograde/Paracrine Release

Retrograde signaling provides an efficient feedback mechanism to enable postsynaptic neurons to communicate with their presynaptic afferents and control transmitter release. It is thought to operate at a variety of synapses throughout the brain and the classical neurotransmitters, neuropeptides, and endocannabinoids have all been identified as retrograde messengers [65]. However, while endocannabinoids operate almost ubiquitously throughout the brain, retrograde activation of presynaptic NMDARs appears, to date, to be confined to select synapses in the cerebellum and hippocampus.

The exact mechanisms that operate to enable retrograde transmitter release and activation of presynaptic NMDARs remain largely unresolved. Even the identity of the retrograde messenger remains elusive. It is presumed to be glutamate or a glutamate-like molecule and may involve reversed operation of glutamate transporters or exocytosis from postsynaptic vesicles.

Generally, the induction of retrograde ‘glutamate’ release requires stimulation of the postsynaptic cell, either directly or by activating afferent inputs, and the influx of Ca2+ [60, 121]. These features are crucial for the expression of a form of inhibitory synaptic plasticity known as depolarization-induced potentiation of inhibition (DPI) at interneuron–Purkinje cell synapses in the cerebellar cortex [32]. Purkinje cell depolarization either directly or by CF activation together with Ca2+ influx was sufficient to ensure the activation of APV-sensitive NMDARs (Figure 14.1D).

The insensitivity of Purkinje cells to NMDA indicated that the locus of NMDAR expression must be presynaptic. This was confirmed by revealing immunoreactivity for NR1 and NR2A through D subunits on interneuronal axon terminals [32]. Subsequently following the activation of presynaptic NMDARs, Ca2+ influx via NMDA channels, but not via voltage–gated Ca2+ channels, induced Ca2+ release from ryanodine-sensitive Ca2+ stores, resulting in increased release of GABA [32]. The presence of functional presynaptic NMDARs was elegantly confirmed by patch clamp recording of single NMDA ion channel activity on basket/stellate cell terminals [39].

The retrograde release of glutamate was not inhibited by glutamate transporter blockers [32], but was substantially reduced by using ligands that disrupt SNARE-dependent vesicular release, e.g., botulinum toxin B, GDP-β-S, or N-ethylmaleimide [31]. Definitive evidence of the source of ‘glutamate’ release was provided by vibromechanically isolating Purkinje cells with attached GABA-releasing inhibitory axon terminals (nerve–bouton preparation [1,110]). The ability to depolarize Purkinje cells and still activate presynaptic NMDARs proved that the retrograde glutamate was released from individual Purkinje cells in preference to surrounding glia [31].

During early development, presynaptic NMDARs located on Schaffer collateral axon terminals on hippocampal CA1 neurons are also modulated by the release of a retrograde messenger. However, unlike in the cerebellum, the messenger involved is not glutamate, but a pregnenolone sulfate (PS)-like neurosteroid synthesized de novo during afferent stimulation [54,74]. The resulting allosteric modulation of presynaptic NMDARs produces a significant enhancement in mEPSC frequency during early hippocampal development (P3–4), probably due to an increase in the probability of release at excitatory synaptic terminals [69]. This neurosteroid modulation disappears during development (>P6), coinciding with a decline in NR2D subunit expression during the first postnatal week in the murine hippocampus [76,114,115]. This association is unexpected because PS potentiates the function of recombinant NR2A or NR2B subunit-containing NMDARs and inhibits those containing NR2C or NR2D subunits [40,68]. Conceivably, the NMDARs on the Schaffer collaterals may possess different NR1 splice variants or form triheteromers with two distinct types of NR2 subunits [69]. Whether this is sufficient to alter modulation by PS remains to be seen.

An alternative mechanism that may be important for the release of glutamate and activation of presynaptic NMDARs involves paracrine secretion from surrounding glial cells [12]. Studies of cultured hippocampal neurons indicated that astrocyte stimulation during ongoing presynaptic activity enhanced the frequency of miniature postsynaptic currents. This was proposed to occur via paracrine release of glutamate activating extrasynaptic (possibly presynaptic) NMDARs to enhance transmitter release [5,6].

This hypothesis is supported by a recent landmark study on astrocyte–neuron signaling at perforant path granule cell (PP-GC) synapses in hippocampal slices [51]. Stimulating the PP released ATP that activated P2Y1 receptors on adjacent glial cells. The increased cytosolic Ca2+ levels caused the vesicular release of a gliotransmitter and increased the frequency of mEPSCs in granule cells. By using immunogold labeling, glutamate was identified as the gliotransmitter since astrocytic vesicles containing glutamate were found directly opposite NR2B subunit-containing NMDARs on PP presynaptic terminals. By using functional and ultrastructural approaches, this study provided definitive evidence for the physiological control of synaptic transmission via exocytosis of glutamate from astrocytes and the corresponding activation of presynaptic NMDARs.

14.6CONCLUSIONS

Go to:

While NMDARs are known for their coincidence detection properties and for underpinning slow EPSPs in central neurons, an increasing number of studies indicate that they have important presynaptic roles in regulating transmitter release. Their location on axon terminals and their ability to initiate a number of Ca2+-dependent signaling mechanisms, from presynaptic transmitter release to phosphorylation of postsynaptic receptors via intermediary messengers, highlights an ever-increasing diversity for presynaptic glutamate receptor signaling at both excitatory and inhibitory synapses.

ACKNOWLEDGMENTS

Go to:

ICD is supported by a Wellcome Trust Advanced Training Fellowship. TGS is supported by grants from the MRC and BBSRC. We thank Alasdair Gibb and Stuart Cull-Candy for comments on the manuscript and Neil Foubister for providing the illustrations.

REFERENCES

Go to:
1.
Akaike N, Moorhouse AJ. Techniques: applications of the nerve-bouton preparation in neuropharmacology. Trends Pharmacol Sci. 2003;24:44. [PubMed: 12498731]
2.
Al Hallaq RA, et al. Association of NR3A with the N-methyl-D-aspartate receptor NR1 and NR2 subunits. Mol Pharmacol. 2002;62:1119. [PubMed: 12391275]
3.
Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia. 2000;32:1. [PubMed: 10975906]
4.
Aoki C, et al. Cellular and subcellular localization of NMDA-R1 subunit immunoreactivity in the visual cortex of adult and neonatal rats. J Neurosci. 1994;14:5202. [PubMed: 8083731]
5.
Araque A, Carmignoto G, Haydon PG. Dynamic signaling between astrocytes and neurons. Annu Rev Physiol. 2001;63:795. [PubMed: 11181976]
6.
Araque A, et al. Calcium elevation in astrocytes causes an NMDAR-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J Neurosci. 1998;18:6822. [PubMed: 9712653]
7.
Auger C, Attwell D. Fast removal of synaptic glutamate by postsynaptic transporters. Neuron. 2000;28:547. [PubMed: 11144363]
8.
Bardoni R, et al. Presynaptic NMDARs modulate glutamate release from primary sensory neurons in rat spinal cord dorsal horn. J Neurosci. 2004;24:2774. [PubMed: 15028770]
9.
Bender VA, et al. Two coincidence detectors for spike timing-dependent plasticity in somatosensory cortex. J Neurosci. 2006;26:4166. [PMC free article: PMC3071735] [PubMed: 16624937]
10.
Berberich S, et al. Lack of NMDAR subtype selectivity for hippocampal long-term potentiation. J Neurosci. 2005;25:6907. [PubMed: 16033900]
11.
Berretta N, Jones RS. Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex. Neuroscience. 1996;75:339. [PubMed: 8931000]
12.
Bezzi P, Volterra A. A neuron-glia signaling network in the active brain. Curr Opin Neurobiol. 2001;11:387. [PubMed: 11399439]
13.
Bliss TV, Collingridge GL, Morris RG. Introduction. Long-term potentiation and structure of the issue. Philos Trans R Soc Lond B Biol Sci. 2003;358:607. [PMC free article: PMC1693168] [PubMed: 12740102]
14.
Brodin L, Christenson J, Grillner S. Single sensory neurons activate excitatory amino acid receptors in the lamprey spinal cord. Neurosci Lett. 1987;75:75. [PubMed: 3033558]
15.
Buchanan JT. Identification of interneurons with contralateral, caudal axons in the lamprey spinal cord: synaptic interactions and morphology. J Neurophysiol. 1982;47:961. [PubMed: 6177842]
16.
Buchanan JT, et al. Reticulospinal neurones activate excitatory amino acid receptors. Brain Res. 1987;408:321. [PubMed: 2885068]
17.
Buchanan JT, Grillner S. Newly identified “glutamate interneurons” and their role in locomotion in the lamprey spinal cord. Science. 1987;236:312. [PubMed: 3563512]
18.
Bustos G, et al. Regulation of excitatory amino acid release by N-methyl-D-aspartate receptors in rat striatum: in vivo microdialysis studies. Brain Res. 1992;585:105. [PubMed: 1355000]
19.
Casado M, Dieudonne S, Ascher P. Presynaptic N-methyl-D-aspartate receptors at the parallel fiber-Purkinje cell synapse. Proc Natl Acad Sci USA. 2000;97:11593. [PMC free article: PMC17245] [PubMed: 11016958]
20.
Casado M, Isope P, Ascher P. Involvement of presynaptic N-methyl-D-aspartate receptors in cerebellar long-term depression. Neuron. 2002;33:123. [PubMed: 11779485]
21.
Chadderton P, Margrie TW, Hausser M. Integration of quanta in cerebellar granule cells during sensory processing. Nature. 2004;428:856. [PubMed: 15103377]
22.
Chazot PL, et al. Molecular characterization of N-methyl-D-aspartate receptors expressed in mammalian cells yields evidence for the coexistence of three subunit types within a discrete receptor molecule. J Biol Chem. 1994;269:24403. [PubMed: 7929101]
23.
Cincotta M, et al. Bidirectional transport of NMDAR and ionophore in the vagus nerve. Eur J Pharmacol. 1989;160:167. [PubMed: 2540989]
24.
Cochilla AJ, Alford S. Glutamate receptor-mediated synaptic excitation in axons of the lamprey. J. Physiol. 1997;499(Pt 2):443. [PMC free article: PMC1159318] [PubMed: 9080373]
25.
Cochilla AJ, Alford S. NMDAR-mediated control of presynaptic calcium and neurotransmitter release. J Neurosci. 1999;19:193. [PubMed: 9870950]
26.
Cull-Candy S, Brickley S, Farrant M. NMDAR subunits: diversity, development and disease. Curr Opin Neurobiol. 2001;11:327. [PubMed: 11399431]
27.
Danysz W, Parsons AC. Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev. 1998;50:597. [PubMed: 9860805]
28.
Das S, et al. Increased NMDA current and spine density in mice lacking the NMDAR subunit NR3A. Nature. 1998;393:377. [PubMed: 9620802]
29.
DeBiasi S, et al. Presynaptic NMDARs in the neocortex are both auto- and hetero-receptors. Neuroreport. 1996;7:2773. [PubMed: 8981465]
30.
Dudel J, Kuffler SW. Presynaptic inhibition at the crayfish neuromuscular junction. J Physiol. 1961;155:543. [PMC free article: PMC1359874] [PubMed: 13724752]
31.
Duguid IC, et al. Somatodendritic release of glutamate regulates synaptic inhibition in cerebellar Purkinje cells via autocrine mGluR1 activation. J Neurosci. 2007;27:12464. [PubMed: 18003824]
32.
Duguid IC, Smart TG. Retrograde activation of presynaptic NMDARs enhances GABA release at cerebellar interneuron-Purkinje cell synapses. Nat Neurosci. 2004;7:525. [PubMed: 15097992]
33.
Eccles JC. Presynaptic inhibition in the spinal cord. Prog Brain Res. 1964;12:65. [PubMed: 14202449]
34.
Eccles JC, Schmidt R, Willis WD. Pharmacological studies on presynaptic inhibition. J Physiol. 1963;168:500. [PMC free article: PMC1359437] [PubMed: 14067941]
35.
Farb CR, Aoki C, Ledoux JE. Differential localization of NMDA and AMPA receptor subunits in the lateral and basal nuclei of the amygdala: a light and electron microscopic study. J Comp Neurol. 1995;362:86. [PubMed: 8576430]
36.
Feng B, et al. Structure-activity analysis of a novel NR2C/NR2D-preferring NMDAR antagonist: 1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid. Br J Pharmacol. 2004;141:508. [PMC free article: PMC1574223] [PubMed: 14718249]
37.
Fink K, Bonisch H, Gothert M. Presynaptic NMDARs stimulate noradrenaline release in the cerebral cortex. Eur J Pharmacol. 1990;185:115. [PubMed: 2171957]
38.
Fischer G, et al. Ro 25-6981 a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. J. Pharmacol. Exp. Ther. 1997;283:1285. [PubMed: 9400004]
39.
Fiszman ML, et al. NMDARs increase the size of GABAergic terminals and enhance GABA release. J Neurosci. 2005;25:2024. [PubMed: 15728842]
40.
Gibbs TT, Russek SJ, Farb DH. Sulfated steroids as endogenous neuromodulators. Pharmacol Biochem Behav. 2006;84:555. [PubMed: 17023038]
41.
Glitsch M, Marty A. Presynaptic effects of NMDA in cerebellar Purkinje cells and interneurons. J Neurosci. 1999;19:511. [PubMed: 9880571]
42.
Gracy KN, Pickel VM. Ultrastructural immunocytochemical localization of the N-methyl-D-aspartate receptor and tyrosine hydroxylase in the shell of the rat nucleus accumbens. Brain Res. 1996;739:169. [PubMed: 8955937]
43.
Hamada T, et al. NMDA induced glutamate release from the suprachiasmatic nucleus: an in vitro study in the rat. Neurosci Lett. 1998;256:93. [PubMed: 9853711]
44.
Hatton CJ, Paoletti P. Modulation of triheteromeric NMDARs by N-terminal domain ligands. Neuron. 2005;46:261. [PubMed: 15848804]
45.
Herkert M, Rottger S, Becker CM. The NMDAR subunit NR2B of neonatal rat brain: complex formation and enrichment in axonal growth cones. Eur J Neurosci. 1998;10:1553. [PubMed: 9751128]
46.
Huang H, Bordey A. Glial glutamate transporters limit spillover activation of presynaptic NMDARs and influence synaptic inhibition of Purkinje neurons. J Neurosci. 2004;24:5659. [PubMed: 15215288]
47.
Humeau Y, et al. Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain. Nature. 2003;426:841. [PubMed: 14685239]
48.
Ito M. Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol Rev. 2001;81:1143. [PubMed: 11427694]
49.
Ito M. The molecular organization of cerebellar long-term depression. Nat Rev Neurosci. 2002;3:896. [PubMed: 12415297]
50.
Johnson KM, Jeng YJ. Pharmacological evidence for N-methyl-D-aspartate receptors on nigrostriatal dopaminergic nerve terminals. Can J Physiol Pharmacol. 1991;69:1416. [PubMed: 1685693]
51.
Jourdain P, et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci. 2007;10:331. [PubMed: 17310248]
52.
Kandel ER, Schwartz JH. Molecular biology of learning: modulation of transmitter release. Science. 1982;218:433. [PubMed: 6289442]
53.
Khakh BS, Henderson G. Modulation of fast synaptic transmission by presynaptic ligand-gated cation channels. J Auton Nerv Syst. 2000;81:110. [PubMed: 10869709]
54.
Kimoto T, et al. Neurosteroid synthesis by cytochrome p450-containing systems localized in the rat brain hippocampal neurons: N-methyl-D-aspartate and calcium-dependent synthesis. Endocrinology. 2001;142:3578. [PubMed: 11459806]
55.
Kirischuk S, Clements JD, Grantyn R. Presynaptic and postsynaptic mechanisms underlie paired pulse depression at single GABAergic boutons in rat collicular cultures. J Physiol. 2002;543:99. [PMC free article: PMC2290498] [PubMed: 12181284]
56.
Krebs MO, et al. Glutamatergic control of dopamine release in the rat striatum: evidence for presynaptic N-methyl-D-aspartate receptors on dopaminergic nerve terminals. J Neurochem. 1991;56:81. [PubMed: 1824785]
57.
Kullmann DM, Asztely F. Extrasynaptic glutamate spillover in the hippocampus: evidence and implications. Trends Neurosci. 1998;21:8. [PubMed: 9464678]
58.
Langer SZ. Presynaptic autoreceptors regulating transmitter release. Neurochem Inc. 2008;52:26.
59.
Lev-Ram V, et al. Synergies and coincidence requirements between NO, cGMP, and Ca2+ in the induction of cerebellar long-term depression. Neuron. 1997;18:1025. [PubMed: 9208868]
60.
Levenes C, Daniel H, Crepel F. Retrograde modulation of transmitter release by postsynaptic subtype 1 metabotropic glutamate receptors in the rat cerebellum. J Physiol. 2001;537:125. [PMC free article: PMC2278923] [PubMed: 11711567]
61.
Lien CC, et al. Visual stimuli-induced LTD of GABAergic synapses mediated by presynaptic NMDARs. Nat Neurosci. 2006;9:372. [PubMed: 16474391]
62.
Liu H, et al. Evidence for presynaptic N-methyl-D-aspartate autoreceptors in the spinal cord dorsal horn. Proc Natl Acad Sci USA. 1994;91:8383. [PMC free article: PMC44610] [PubMed: 8078891]
63.
Liu L, et al. Role of NMDAR subtypes in governing the direction of hippocampal synaptic plasticity. Science. 2004;304:1021. [PubMed: 15143284]
64.
Liu SJ, Lachamp P. The activation of excitatory glutamate receptors evokes a long-lasting increase in the release of GABA from cerebellar stellate cells. J Neurosci. 2006;26:9332. [PubMed: 16957089]
65.
Ludwig M, Pittman QJ. Talking back: dendritic neurotransmitter release. Trends Neurosci. 2003;26:255. [PubMed: 12744842]
66.
Luscher C, et al. Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nat Neurosci. 2000;3:545. [PubMed: 10816309]
67.
MacDermott AB, Role LW, Siegelbaum SA. Presynaptic ionotropic receptors and the control of transmitter release. Annu Rev Neurosci. 1999;22:443. [PubMed: 10202545]
68.
Malayev A, Gibbs TT, Farb DH. Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDARs by sulphated steroids. Br J Pharmacol. 2002;135:901. [PMC free article: PMC1573207] [PubMed: 11861317]
69.
Mameli M, et al. Neurosteroid-induced plasticity of immature synapses via retrograde modulation of presynaptic NMDARs. J Neurosci. 2005;25:2285. [PubMed: 15745954]
70.
Marcaggi P, Attwell D. Short- and long-term depression of rat cerebellar parallel fibre synaptic transmission mediated by synaptic crosstalk. J Physiol. 2007;578:545. [PMC free article: PMC2075140] [PubMed: 17110417]
71.
Martin D, et al. Autoreceptor regulation of glutamate and aspartate release from slices of the hippocampal CA1 area. J Neurochem. 1991;56:1647. [PubMed: 1672884]
72.
Mayer ML, Armstrong N. Structure and function of glutamate receptor ion channels. Annu Rev Physiol. 2004;66:161. [PubMed: 14977400]
73.
McBain CJ, Mayer ML. N-methyl-D-aspartic acid receptor structure and function. Physiol Rev. 1994;74:723. [PubMed: 8036251]
74.
Mellon SH, Vaudry H. Biosynthesis of neurosteroids and regulation of their synthesis. Int Rev Neurobiol. 2001;46:33. [PubMed: 11599305]
75.
Mott DD, et al. Phenylethanolamines inhibit NMDARs by enhancing proton inhibition. Nat Neurosci. 1998;1:659. [PubMed: 10196581]
76.
Okabe S, et al. Hippocampal synaptic plasticity in mice overexpressing an embryonic subunit of the NMDAR. J Neurosci. 1998;18:4177. [PubMed: 9592097]
77.
Ozawa S. Role of glutamate transporters in excitatory synapses in cerebellar Purkinje cells. Brain Nerve. 2007;59:669. [PubMed: 17663137]
78.
Ozawa S, Kamiya H, Tsuzuki K. Glutamate receptors in the mammalian central nervous system. Prog Neurobiol. 1998;54:581. [PubMed: 9550192]
79.
Paoletti P, Ascher P, Neyton J. High-affinity zinc inhibition of NMDA NR1-NR2A receptors. J Neurosci. 1997;17:5711. [PubMed: 9221770]
80.
Paoletti P, Neyton J. NMDAR subunits: function and pharmacology. Curr Opin Pharmacol. 2007;7:39. [PubMed: 17088105]
81.
Paquet M, Smith Y. Presynaptic NMDAR subunit immunoreactivity in GAB-Aergic terminals in rat brain. J Comp Neurol. 2000;423:330. [PubMed: 10867662]
82.
Petralia RS, Wang YX, Wenthold RJ. The NMDAR subunits NR2A and NR2B show histological and ultrastructural localization patterns similar to those of NR1. J Neurosci. 1994;14:6102. [PubMed: 7931566]
83.
Petralia RS, Yokotani N, Wenthold RJ. Light and electron microscope distribution of the NMDAR subunit NMDAR1 in the rat nervous system using a selective anti-peptide antibody. J Neurosci. 1994;14:667. [PubMed: 8301357]
84.
Pina-Crespo JC, Gibb AJ. Subtypes of NMDARs in new-born rat hippocampal granule cells. J Physiol. 2002;541:41. [PMC free article: PMC2290300] [PubMed: 12015419]
85.
Piochon C, et al. NMDAR contribution to the climbing fiber response in the adult mouse Purkinje cell. J Neurosci. 2007;27:10797. [PubMed: 17913913]
86.
Pittaluga A, Raiteri M. N-methyl-D-aspartic acid (NMDA) and non-NMDARs regulating hippocampal norepinephrine release. I. Location on axon terminals and pharmacological characterization. J Pharmacol Exp Ther. 1992;260:232. [PubMed: 1370540]
87.
Quinlan EM, et al. Rapid, experience-dependent expression of synaptic NMDARs in visual cortex in vivo. Nat Neurosci. 1999;2:352. [PubMed: 10204542]
88.
Rachline J, et al. The micromolar zinc-binding domain on the NMDAR subunit NR2B. J Neurosci. 2005;25:308. [PubMed: 15647474]
89.
Raditsch M, et al. Subunit-specific block of cloned NMDARs by argiotoxin-636. FEBS Lett. 1993;324:63. [PubMed: 8099331]
90.
Raiteri M. Functional pharmacology in human brain. Pharmacol Rev. 2006;58:162. [PubMed: 16714485]
91.
Renzi M, Farrant M, Cull-Candy SG. Climbing-fibre activation of NMDARs in Purkinje cells of adult mice. J Physiol. 2007;585:91. [PMC free article: PMC2327252] [PubMed: 17901118]
92.
Robert A, Black JA, Waxman SG. Endogenous NMDA-receptor activation regulates glutamate release in cultured spinal neurons. J Neurophysiol. 1998;80:196. [PubMed: 9658041]
93.
Sasaki YF, et al. Characterization and comparison of the NR3A subunit of the NMDAR in recombinant systems and primary cortical neurons. J Neurophysiol. 2002;87:2052. [PubMed: 11929923]
94.
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci. 2001;22:565. [PubMed: 11698100]
95.
Shigeri Y, et al. Effects of threo-beta-hydroxyaspartate derivatives on excitatory amino acid transporters (EAAT4 and EAAT5). J Neurochem. 2001;79:297. [PubMed: 11677257]
96.
Shimamoto K, et al. DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters. Mol Pharmacol. 1998;53:195. [PubMed: 9463476]
97.
Shin JH, Linden DJ. An NMDAR/nitric oxide cascade is involved in cerebellar LTD but is not localized to the parallel fiber terminal. J Neurophysiol. 2005;94:4281. [PubMed: 16120658]
98.
Siegel SJ, et al. Regional, cellular, and ultrastructural distribution of N-methyl-D-aspartate receptor subunit 1 in monkey hippocampus. Proc Natl Acad Sci USA. 1994;91:564. [PMC free article: PMC42989] [PubMed: 8290563]
99.
Sjostrom PJ, Turrigiano GG, Nelson SB. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron. 2003;39:641. [PubMed: 12925278]
100.
Smart TG, Hosie AM, Miller PS. Zn2+ ions: modulators of excitatory and inhibitory synaptic activity. Neuroscientist. 2004;10:432. [PubMed: 15359010]
101.
Smart TG, Xie X, Krishek BJ. Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc. Prog Neurobiol. 1994;42:393. [PubMed: 7520185]
102.
Stevens CF. Neurotransmitter release at central synapses. Neuron. 2003;40:381. [PubMed: 14556715]
103.
Stevens CF. Presynaptic function. Curr Opin Neurobiol. 2004;14:341. [PubMed: 15194114]
104.
Suarez LM, Solis JM. Taurine potentiates presynaptic NMDARs in hippocampal Schaffer collateral axons. Eur J Neurosci. 2006;24:405. [PubMed: 16836643]
105.
Sudhof TC. The synaptic vesicle cycle. Annu Rev Neurosci. 2004;27:509. [PubMed: 15217342]
106.
Tovar KR, Westbrook GL. The incorporation of NMDARs with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci. 1999;19:4180. [PubMed: 10234045]
107.
Traynelis SF, et al. Control of voltage-independent zinc inhibition of NMDARs by the NR1 subunit. J Neurosci. 1998;18:6163. [PubMed: 9698310]
108.
Tzingounis AV, Wadiche JI. Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nat Rev Neurosci. 2007;8:935. [PubMed: 17987031]
109.
Vesselkin NP, et al. Ultrastructural study of glutamate- and GABA-immunoreactive terminals contacting the primary afferent fibers in frog spinal cord. A double postembedding immunocytochemical study. Brain Res. 2003;960:267. [PubMed: 12505682]
110.
Vorobjev VS. Vibrodissociation of sliced mammalian nervous tissue. J Neurosci Meth. 1991;38:145.
111.
Wang H, Pickel VM. Presence of NMDA-type glutamate receptors in cingulate corticostriatal terminals and their postsynaptic targets. Synapse. 2000;35:300. [PubMed: 10657040]
112.
Wang JK. Presynaptic glutamate receptors modulate dopamine release from striatal synaptosomes. J Neurochem. 1991;57:819. [PubMed: 1650394]
113.
Wenzel A, et al. N-methyl-D-aspartate receptors containing the NR2D subunit in the retina are selectively expressed in rod bipolar cells. Neuroscience. 1997;78:1105. [PubMed: 9174077]
114.
Wenzel A, et al. Distribution of NMDAR subunit proteins NR2A, 2B, 2C and 2D in rat brain. NeuroReport. 1995;7:45. [PubMed: 8742413]
115.
Wenzel A, et al. Developmental and regional expression of NMDAR subtypes containing the NR2D subunit in rat brain. J Neurochem. 1996;66:1240. [PubMed: 8769890]
116.
Williams K. Ifenprodil discriminates subtypes of N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol. 1993;44:851. [PubMed: 7901753]
117.
Woodhall G, et al. NR2B-containing NMDA autoreceptors at synapses on entorhinal cortical neurons. J Neurophysiol. 2001;86:1644. [PubMed: 11600627]
118.
Yamakura T, et al. Different sensitivities of NMDAR channel subtypes to non-competitive antagonists. NeuroReport. 1993;4:687. [PubMed: 8347808]
119.
Yamakura T, Shimoji K. Subunit- and site-specific pharmacology of the NMDAR channel. Prog Neurobiol. 1999;59:279. [PubMed: 10465381]
120.
Yang J, Woodhall GL, Jones RS. Tonic facilitation of glutamate release by presynaptic NR2B-containing NMDARs is increased in the entorhinal cortex of chronically epileptic rats. J Neurosci. 2006;26:406. [PMC free article: PMC2504723] [PubMed: 16407536]
121.
Zilberter Y. Dendritic release of glutamate suppresses synaptic inhibition of pyramidal neurons in rat neocortex. J Physiol. 2000;528:489. [PMC free article: PMC2270153] [PubMed: 11060126]

Copyright © 2009, Taylor & Francis Group, LLC.

Print View 
Cover of Biology of the NMDA Receptor
Biology of the NMDA Receptor.
Van Dongen AM, editor.
Boca Raton (FL): CRC Press; 2009.

In this Page

Other titles in this collection

Related information

Related citations in PubMed

See reviews... See all...

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...
You are here: NCBI > Literature > Bookshelf
Write to the Help Desk