Glutamate
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| Papouin et al 2012 | Glycine affinity 10x greater for GluN2B>GluN2A, d-serine similar. Glycine seems to act out of synapse, d-serine acts in synapse. Selective block of gly specific subunit (GluN2B) decr %age block in absence of glycine, incr %age block in absence of D-serine
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| Agulhon et al 2010 | Astrocyte Ca manipulation had no effect on release, Gq and Ca were thought to be involved. Couldnt find any evidence for astrotransmission in these experiments, maybe cos they transfected in a Gq GPCR to stim, might not be coupled to channels
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| Fremeau et al 2004 | VGLUT1 is found in separate neurons to those expressing VGLUT2. Seems that rarely used synpases with high potential for plasticity use VGLUT1. VGLUT3 found outside the brain & in scattered interneurons thought to release Glutamate & GABA.
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| Harkany et al 2004 | CB receptors not involved in inhibition between interneurouns and layer 2/3 pyraidal cells, no immunolabel. Glutamate retrograde signalling via mGluRs, found VGLUT3 by mRNA In-situ hybrid, disrupting VGLUTs disrupted retro signalling. mGlu agonists work
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| Perea & Araque 2007 | Evidence for gliotransmission, showed Ca incr in astrocytes raised probability of transmitter release at CA3-CA1 synapses. Used photostimulation of astrocytes. ATP caused similar changes (A1Rs blocked to factor out adenosine). Small numbers used.
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| Woo et al 2012 | TREK-1 & Best1 channels allow non-vesicle release of glutamate in astrocytes. Uses sniffer cell with non-desensitising AMPARs. Fast release is Ca independent, slow rel reqs Ca. BEST is slow mode, TREK-1 is fast, used shRNA to reduce. Pro-gliotransmission
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| Conflict over astrotransmission | Agulhon 2010 is against, Woo 2012 is pro, Perea 2007 is pro. May depend on method of stimulation used. Woo is fairly convincing.
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| Henley et al 2011 | Insertion of AMPARs is PKA dependent. Ca enhances binding of PICK1 to GluA2 and vesicle fusion protein (β-SNAP) to promote endocyt of PKC modified GluA2. Loss of clathrin reduces transmission as receptors diffuse away from synapse (less endocyt). Gd paper
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| Liu & Cull-Candy 2000 | Calcium influxes through V-G Ca channels result in incr GluR2 expression, making AMPARs less permeable. Used sel antagonists and I/V plots to show changes in GluR2 expression. Blocking Ca entry with TTX makes IV graph linear as Ca permeability increases
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| Tomita et al 2005 | Stargazin slows channel deactivation and desensitisation. Mutated in stargazer mice with absence epilepsy. Cytoplasmic domain slows trafficking, extracellular domain affects gating. Transfection into xenopus oocytes.
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| Contractor et al 2001 | LTP reduced in mice lacking GluK2 & 3, not GluK1. Forskolin still induces LTP, must act downstream. mGluR1 antag removed remaining LTP (presume 2 pathways). Less high freq potentiation thought to be due to less Ca entry through presyn kainate receptors.
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| Zhang et al 2009 | NETO2 interacts with kainate receptors, incr open probability, decr decay. Altered agonist sensitivity in heterologous cells. Found by co-IP. NETO acts like TARPs do with AMPARs but looks different.
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| Chatterton et al 2002 | NR3A/B can complex with NR1 subunits to make excitatory glycine receptors. Relatively impermeable to Ca. Mg block more easily removed. D-serine partial agonist. Inhibitors at glutamate binding site no longer effective
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| Renden et al 2005 | Glutamate transporters terminate the EPSC at enclosed synapses, open synapses rely on diffusion. Some synapses may use desensitisation as the shut-off. mGluR2 may decr future release by pre-synaptic action. Passive diff most important in young & old
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| Tzingounis & Wadiche 2007 | EAATs are glutamate transporters. 1&2 are mainly glial, 3,4&5 are neural (5 in retina, 4 in purkinje cells). Can end transmission or prevent spread to extracellular. Uptake upreg in LTP. EAATs mainly buffers due to slow rate, less important in transport
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| Nakanishi et al 2009 | GluN3 subunit causes reduced current and protects against excitotoxicity as shown by knockout and overexpression both in vivo & ex vivo. GluN3 shown to be dysregulated in bipolar disorder & schizophrenia.
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| Nowak et al 1984 & Mayer et al 1984 | Showed separately that Mg2+ was capable of inhibiting the NMDA receptor. Nowak used MG free solutions and showed a reduced block. Mayer did same, both used voltage clamp
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| Schell et al 1995 | Showed D-serine could be an endogenous agonist. First showed that it colocalised with NMDA receptors. Then showed that AMPA and kainate augment d-serine release (radiolabelled)
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| Johnson & Ascher 1987 | Showed that glycine was required for NMDA opening, observed reduced activation at high perfusion and hypothesised that something was being washed away. Tried all amino acids to test potentiation + characterised unknown substance for heat resistance etc.
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| Henneberger et al 2010 | D-serine is produced by astrocytes. Found that Ca clamping prevented the release and disrupted LTP. EGTA did not prevent LTP (and thus d-serine release) in other studies
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| Ge & Duan 2007 | Shows that loading astrocytes with EGTA fails to prevent LTP indicating that the factor released is released Ca-independently (presume d-serine)
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| Matsui et al 1995 | d-serine has a 3x lower ED50 than glycine. Also shows d-serine is saturating at physiological concentrations in the frontal cortex (levels measured by microdialysis) - Abstract only
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| Mothet et al 2000 | Addition of an enzyme to degrade d-serine has physiologically relevant actions in the hippocampus. Doesnt prove glycine isnt acting too, would require same experiment, different enzyme (for glycine). Adding D-serine also incr activity away from synapse
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| Pina-Crespo et al 2010 | Shows that d-serine/glycine mediates excitatory currents in optic nerve myelin, currents abolished by KO of GluNR3 subunit. Used immunoblot to show NR1 and NR3 complexed together. No response to glutamate antagonist APV
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| Moskal et al 2011 | Says genes linked to autism in humans and rat models are often involved with the NMDA receptor. Also shows normalisation of rat behaviour using an NMDA partial agonist at the glycine site. Rats made more pro-social ultrasonic vocalisations.
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| Erhardt et al 2009 | Shows drugs acting at the NMDA glycine binding site may have a use in treatment of schizophrenia. Abstract only.
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| Billups & Attwell 1996 | Low pH in ischaemia inhibits the EAAT and prevents its reversal (due to loss of Na/K/electro gradients). Used sniffer cell. Thus the low pH is protective in ischaemia, enhancing block pharmacologically may be beneficial.
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| Kubokawa et al 1996 | Shows a salmon homologue of mGluR activated by both glutamate and calcium, first description of a metabotropic receptor activated by two completely different physiological ligands. Found through chloride channel ability of the mGluR
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| Kubo et al 1998 | Several rat homologues of mGluR (seems to be a fairly common property of the family). Saturating concentrations of either agonist did not prevent response to the other, indicates distinct binding sites.
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| Storm-Mathisen & Iversen 1979 | [3H]glutamate is concentrated in glutamatergic terminals when added to extracellular soln. Suggests EAATs on presynaptic cell, no known EAATs are expressed by glutamatergic terminals. Storm-Ma showed 2 years prev that axotomy reduced uptake around synapse
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| Moechars et al 2006 | VGLUT2 +/- mice have attenuated neuropathic pain (spared nerve injury) and less anxiety-related behaviour. Normal memory and acute pain. VGLUT2 decr in thalamus thought to be important, peripheral nerves can compensate with VGLUT1. -/- was embryolethal.
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| Lu et al 2006 | Introduced cre to indiv CA1 neurons in which specific subunits of AMPARs had been floxed. Found 80% of synaptic and 95% of extrasyn receptors are GLUA1/2, remainder are GLUA2/3 (in these neurons). Some GLUA2-/- synapses compensate over time, others dont
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| Hirbec et al 2003 | Kainate receptors interact with PICK (CoIP and yeast 2 hybrid), and through it PKC. Preventing either interaction decreased kainate receptor surface expression.
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| Rodriguez-Moreno & Lerma 1998 | Some kainate activity due to Ptx sensitive G protein (Gi). Less inhib of a GABA IPSC after pertussis toxin or PKC blocker. Kainate as agonist, NMDA+AMPA blocked. Non-conducting Na-substitute had no effect. T1mGluR agonist had no effect on kainate response
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