Facilitation of Spinal NMDA Receptor Currents by Spillover of Synaptically Released Glycine

Ahmadi, Seifollah; Muth-Selbach, Uta; Lauterbach, Andreas; Lipfert, P.; Neuhuber, Winfried; Zeilhofer, Hanns Ulrich

doi:10.1126/science.1083970

Cited by 130 publications

(107 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…D. Burrell, unpublished observations), possibly because application of sufficient amounts of glycine alone can induce LTP (Musleh et al, 1997;Lu et al, 2001;Man et al, 2003). This requirement for phasic application of glycine suggests that its extracellular concentration is regulated in the leech brain as occurs in the vertebrate CNS (Schell et al, 1995;Supplisson and Bergman, 1997;Ahmadi et al, 2003;Yang et al, 2003), but that some element of the experimental protocol disrupted this process.…”

Section: Discussionmentioning

confidence: 99%

Multiple Forms of Long-Term Potentiation and Long-Term Depression Converge on a Single Interneuron in the Leech CNS

Burrell¹,

Sahley²

2004

J. Neurosci.

View full text Add to dashboard Cite

Long-term potentiation (LTP) of synaptic transmission was observed in two types of synapses that converge on the same postsynaptic neuron in the leech CNS. These synapses were made by identifiable sensory neurons, the mechanosensory touch (T-) and pressure (P-) cells, onto the S-cell, an interneuron critical for certain forms of learning. Changes in both the T-S and P-S synapses appear to be activity dependent because LTP was restricted to inputs that had undergone tetanization; however, properties of synaptic plasticity at the T-S and P-S connections differ considerably. At the P-S synapse, LTP was induced in the tetanized synapse but not in the nontetanized synapse tested in parallel. P-S LTP was blocked by the NMDA receptor antagonist DL-2-amino-5-phosphono-valeric acid (AP-5) or by lowering the extracellular concentration of glycine, an NMDA receptor (NMDAR) co-agonist. P-S LTP was strongly affected by the initial amplitude of the synaptic potential at the time LTP was induced. Smaller amplitude synapses (Ͻ3.5 mV) underwent robust potentiation, whereas the less common, larger amplitude synapse (Ͼ3.5 mV) depressed after tetanization. At the T-S synapse, tetanization simultaneously induced homosynaptic LTP in the tetanized input and heterosynaptic long-term depression (LTD) in the input made by a nontetanized T-cell onto the same S-cell. Interestingly, AP-5 failed to block homosynaptic LTP at the T-S synapse but did prevent heterosynaptic LTD. T-S LTP was not affected by the initial EPSP amplitude. Thus, leech neurons exhibit synaptic plasticity with properties similar to LTP and LTD found in the vertebrate nervous system.

show abstract

Section: Discussionmentioning

confidence: 99%

Multiple Forms of Long-Term Potentiation and Long-Term Depression Converge on a Single Interneuron in the Leech CNS

Burrell¹,

Sahley²

2004

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…During intense nociceptive input, glycine released from inhibitory interneurons can escape the synaptic cleft and reach adjacent NMDA receptors by spillover, hence facilitating excitatory neurotransmission. Suppression of this process can also induce analgesia (76). Therefore, it has been reported that manipulation of the synaptic glycine concentrations affects nociception by influencing both excitatory and inhibitory transmission.…”

Section: Discussionmentioning

confidence: 99%

P2Y Purinergic Regulation of the Glycine Neurotransmitter Transporters

Jiménez

Zafra

Pérez-Sen

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The sodium-and chloride-coupled glycine neurotransmitter transporters (GLYTs) control the availability of glycine at glycine-mediated synapses. The mainly glial GLYT1 is the key regulator of the glycine levels in glycinergic and glutamatergic pathways, whereas the neuronal GLYT2 is involved in the recycling of synaptic glycine from the inhibitory synaptic cleft. In this study, we report that stimulation of P2Y purinergic receptors with 2-methylthioadenosine 5 -diphosphate in rat brainstem/spinal cord primary neuronal cultures and adult rat synaptosomes leads to the inhibition of GLYT2 and the stimulation of GLYT1 by a paracrine regulation. These effects are mainly mediated by the ADP-preferring subtypes P2Y 1 and P2Y 13 because the effects are partially reversed by the specific antagonists N 6 -methyl-2 -deoxyadenosine-3 ,5 -bisphosphate and pyridoxal-5 -phosphate-6-azo(2-chloro-5-nitrophenyl)-2,4-disulfonate and are totally blocked by suramin. P2Y 12 receptor is additionally involved in GLYT1 stimulation. Using pharmacological approaches and siRNAmediated protein knockdown methodology, we elucidate the molecular mechanisms of GLYT regulation. Modulation takes place through a signaling cascade involving phospholipase C activation, inositol 1,4,5-trisphosphate production, intracellular Ca 2؉ mobilization, protein kinase C stimulation, nitric oxide formation, cyclic guanosine monophosphate production, and protein kinase G-I (PKG-I) activation. GLYT1 and GLYT2 are differentially sensitive to NO/cGMP/PKG-I both in brain-derived preparations and in heterologous systems expressing the recombinant transporters and P2Y 1 receptor. Sensitivity to 2-methylthioadenosine 5 -diphosphate by GLYT1 and GLYT2 was abolished by small interfering RNA (siRNA)-mediated knockdown of nitric-oxide synthase. Our data may help define the role of GLYTs in nociception and pain sensitization.

show abstract

“…In structures where glycinergic innervation is abundant, such as in the retina and the spinal cord, glycine that serves as an endogenous co-agonist at NMDARs originates from glycinergic terminals [70,71]. In those preparations, it was demonstrated that glycine released at inhibitory synapses spills over and diffuses to bind to remote NMDARs.…”

Section: Co-agonist Control Of Extrasynaptic Nmdarsmentioning

confidence: 99%

Organization, control and function of extrasynaptic NMDA receptors

Papouin

Oliet

2014

Phil. Trans. R. Soc. B

154

123

View full text Add to dashboard Cite

N-methyl D-aspartate receptors (NMDARs) exist in different forms owing to multiple combinations of subunits that can assemble into a functional receptor. In addition, they are located not only at synapses but also at extrasynaptic sites. There has been intense speculation over the past decade about whether specific NMDAR subtypes and/or locations are responsible for inducing synaptic plasticity and excitotoxicity. Here, we review the latest findings on the organization, subunit composition and endogenous control of NMDARs at extrasynaptic sites and consider their putative functions. Because astrocytes are capable of controlling NMDARs through the release of gliotransmitters, we also discuss the role of the glial environment in regulating the activity of these receptors.

show abstract

Facilitation of Spinal NMDA Receptor Currents by Spillover of Synaptically Released Glycine

Cited by 130 publications

References 24 publications

Multiple Forms of Long-Term Potentiation and Long-Term Depression Converge on a Single Interneuron in the Leech CNS

Multiple Forms of Long-Term Potentiation and Long-Term Depression Converge on a Single Interneuron in the Leech CNS

P2Y Purinergic Regulation of the Glycine Neurotransmitter Transporters

Organization, control and function of extrasynaptic NMDA receptors

Contact Info

Product

Resources

About