Showing papers on "Kainate receptor published in 2006"
TL;DR: The finding that the Ca2+ increase was mediated in large part by activation of myelinic NMDA receptors suggests a new mechanism of axo–myelinic signalling, which may represent a potentially important therapeutic target in disorders in which demyelination is a prominent feature.
Abstract: Central nervous system myelin is a specialized structure produced by oligodendrocytes that ensheaths axons, allowing rapid and efficient saltatory conduction of action potentials1 Many disorders promote damage to and eventual loss of the myelin sheath, which often results in significant neurological morbidity However, little is known about the fundamental mechanisms that initiate myelin damage, with the assumption being that its fate follows that of the parent oligodendrocyte Here we show that NMDA (N-methyl-d-aspartate) glutamate receptors mediate Ca2+ accumulation in central myelin in response to chemical ischaemia in vitro Using two-photon microscopy, we imaged fluorescence of the Ca2+ indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the myelin sheath in adult rat optic nerves The AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptor antagonist NBQX2 completely blocked the ischaemic Ca2+ increase in oligodendroglial cell bodies, but only modestly reduced the Ca2+ increase in myelin In contrast, the Ca2+ increase in myelin was abolished by broad-spectrum NMDA receptor antagonists (MK-801, 7-chlorokynurenic acid, d-AP53,4), but not by more selective blockers of NR2A and NR2B subunit-containing receptors (NVP-AAM0775 and ifenprodil2,4) In vitro ischaemia causes ultrastructural damage to both axon cylinders and myelin6 NMDA receptor antagonism greatly reduced the damage to myelin NR1, NR2 and NR3 subunits were detected in myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits are present for the formation of functional NMDA receptors Our data show that the mature myelin sheath can respond independently to injurious stimuli Given that axons are known to release glutamate7,8,9, our finding that the Ca2+ increase was mediated in large part by activation of myelinic NMDA receptors suggests a new mechanism of axo–myelinic signalling Such a mechanism may represent a potentially important therapeutic target in disorders in which demyelination is a prominent feature, such as multiple sclerosis, neurotrauma, infections (for example, HIV encephalomyelopathy) and aspects of ischaemic brain injury
476 citations
TL;DR: It is shown that chemically induced long-term potentiation (chemLTP) drives robust exocytosis of AMPA receptors and produces similar modification of small and large spines during chemLTP induction, indicating that distinct mechanisms underlie changes in morphology and receptor content.
Abstract: The changes in synaptic morphology and receptor content that underlie neural plasticity are poorly understood. Here, we use a pH-sensitive green fluorescent protein to tag recombinant glutamate receptors and monitor their dynamics onto dendritic spine surfaces. We show that chemically induced long-term potentiation (chemLTP) drives robust exocytosis of AMPA receptors. In contrast, the same stimulus produces a small reduction of NMDA receptors from the spine surface. chemLTP produces similar modification of small and large spines. Interestingly, during chemLTP induction, spines increase in volume before accumulation of AMPA receptors on their surface, indicating that distinct mechanisms underlie changes in morphology and receptor content.
475 citations
TL;DR: The pivotal role that TARPs play in the life cycle of AMPA receptors is reviewed and it is shown that a family of small transmembrane AMPA receptor regulatory proteins (TARPs) controls both AMPAceptor trafficking and channel gating.
Abstract: Glutamate, the major excitatory neurotransmitter in the brain, acts primarily on two types of ionotropic receptors: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and N -methyl-d-aspartate (NMDA) receptors. Work over the past decade indicates that regulated changes in the number of synaptic AMPA receptors may serve as a mechanism for information storage. Recent studies demonstrate that a family of small transmembrane AMPA receptor regulatory proteins (TARPs) controls both AMPA receptor trafficking and channel gating. TARPs provide the first example of auxiliary subunits of ionotropic receptors. Here we review the pivotal role that TARPs play in the life cycle of AMPA receptors.
363 citations
TL;DR: This review focuses on the role of glutamate receptors, including both ionotropic (AMPA, NMDA and kainate) and metabotropic (mGlu1-8) receptors in persistent pain states with particular emphasis on their expression patterns in nociceptive pathways and their potential as targets for pharmacological intervention strategies.
279 citations
TL;DR: The results suggest that neurons are a major source of d-Serine, and Glutamate-induced neuronal d-serine release provides a novel mechanism for activating NMDA receptors by an autocrine or paracrine way.
264 citations
TL;DR: Insight into the molecular pathways that mediate perinatal brain injuries could lead to therapeutic interventions and suggest that some of these intracellular pathways are sexually dimorphic.
Abstract: Excitotoxicity is an important mechanism involved in perinatal brain injuries. Glutamate is the major excitatory neurotransmitter, and most neurons as well as many oligodendrocytes and astrocytes possess receptors for glutamate. Perinatal insults such as hypoxia-ischemia, stroke, hypoglycemia, kernicterus, and trauma can disrupt synaptic function leading to accumulation of extracellular glutamate and excessive stimulation of these receptors. The activities of certain glutamate receptor/channel complexes are enhanced in the immature brain to promote activity-dependent plasticity. Excessive stimulation of glutamate receptor/ion channel complexes triggers calcium flooding and a cascade of intracellular events that results in apoptosis and/or necrosis. Recent research suggests that some of these intracellular pathways are sexually dimorphic. Age dependent expression of different glutamate receptor subtypes with varying abilities to flux calcium has been associated with special patterns of selective vulnerability at different gestational ages. For example, selective injury to the putamen, thalamus and cerebral cortex from near total asphyxia in term infants may be related to excessive activation of neuronal NMDA and AMPA type glutamate receptors, while brain-stem injury may be related primarily to stimulation of neuronal AMPA/kainate receptors. In contrast, periventricular leukomalacia in premature infants has been linked to expression of AMPA/kainate receptors on immature oligodendrocytes. Insight into the molecular pathways that mediate perinatal brain injuries could lead to therapeutic interventions.
255 citations
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TL;DR: Development of antagonists binding to specific protein subunits is currently enabling precise identification of discrete iGlu or mGlu receptor subtypes that participate in a range of central synaptic processes, including synaptic plasticity.
Abstract: Glutamatergic synaptic transmission in the mammalian central nervous system was slowly established over a period of some 20 years, dating from the 1950s. Realisation that glutamate and like amino acids (collectively known as excitatory amino acids (EAA)) mediated their excitatory actions via multiple receptors preceded establishment of these receptors as synaptic transmitter receptors. EAA receptors were initially classified as N-methyl-D-aspartate (NMDA) and non-NMDA receptors, the latter subdivided into quisqualate (later AMPA) and kainate receptors after agonists that appeared to activate these receptors preferentially, and by their sensitivity to a range of differentially acting antagonists developed progressively during the 1970s. NMDA receptors were definitively shown to be synaptic receptors on spinal neurones by the sensitivity of certain excitatory pathways in the spinal cord to a range of specific NMDA receptor antagonists. Importantly, specific NMDA receptor antagonists appeared to be less effective at synapses in higher centres. In contrast, antagonists that also blocked non-NMDA as well as NMDA receptors were almost universally effective at blocking synaptic excitation within the brain and spinal cord, establishing both the existence and ubiquity of non-NMDA synaptic receptor systems throughout the CNS. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways, acting in concert with non-NMDA receptors under conditions where a protracted excitatory postsynaptic potential was effected in response to intense stimulation of presynaptic fibres. Such activation of NMDA receptors together with non-NMDA receptors led to the phenomenon of long-term potentiation (LTP), associated with lasting changes in synaptic efficacy (synaptic plasticity) and considered to be an important process in memory and learning. During the 1980s, it was shown that certain glutamate receptors in the brain mediated biochemical changes that were not susceptible to NMDA or non-NMDA receptor antagonists. This dichotomy was resolved in the early 1990s by the techniques of molecular biology, which identified two families of glutamate-binding receptor proteins (ionotropic (iGlu) and metabotropic (mGlu) receptors). Development of antagonists binding to specific protein subunits is currently enabling precise identification of discrete iGlu or mGlu receptor subtypes that participate in a range of central synaptic processes, including synaptic plasticity.
250 citations
TL;DR: Findings support the hypothesis that BMAA may contribute to the selective MN loss in ALS/PDC and indicate that cycad seed extracts triggered preferential AMPA/kainate-receptor-dependent MN injury, consistent with the idea that BM AA is a crucial toxic component in this plant.
245 citations
TL;DR: It is shown that both zinc and copper ions have a number of actions on selected members of the voltage-gated-like ion channel superfamily, which may contribute to the etiology of certain disease states such as Alzheimer's disease (AD) and epilepsy.
239 citations
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TL;DR: Kainate receptors form a family of ionotropic glutamate receptors that appear to play a special role in the regulation of the activity of synaptic networks as mentioned in this paper, and they are involved in synaptic integration, synaptic plasticity, regulation of neurotransmitter release and the control of neuronal excitability.
Abstract: Kainate receptors form a family of ionotropic glutamate receptors that appear to play a special role in the regulation of the activity of synaptic networks. This review first describes briefly the molecular and pharmacological properties of native and recombinant kainate receptors. It then attempts to outline the general principles that appear to govern the function of kainate receptors in the activity of synaptic networks under physiological conditions. It subsequently describes the way that kainate receptors are involved in synaptic integration, synaptic plasticity, the regulation of neurotransmitter release and the control of neuronal excitability, and the manner in which they might play an important role in synaptogenesis and synaptic maturation. These functions require the proper subcellular localization of kainate receptors in specific functional domains of the neuron, necessitating complex cellular and molecular trafficking events. We show that our comprehension of these mechanisms is just starting to emerge. Finally, this review presents evidence that implicates kainate receptors in pathophysiological conditions such as epilepsy, excitotoxicity and pain, and that shows that these receptors represent promising therapeutic targets.
225 citations
TL;DR: G-protein-dependent signaling is crucial for AMPA-stimulated migration of OPCs but not for basal OPC migration, and it is suggested that glutamate could play a pivotal role in regulating integrin-mediated O PC migration.
Abstract: In the mammalian CNS, oligodendrocyte precursor cells (OPCs) express most neurotransmitter receptors, but their function remains unclear. The current studies suggest a physiological role for glutamate (AMPA and/or kainate) receptors in OPC migration. AMPA stimulated αv integrin-mediated OPC migration by increasing both the rate of cell movement and the frequency of Ca2+ transients. A protein complex containing the myelin proteolipid protein (PLP) and αv integrin modulated the AMPA-stimulated migration, and stimulation of OPC AMPA receptors resulted in increased association of the AMPA receptor subunits themselves with the αv integrin/PLP complex. Thus, after AMPA receptor stimulation, an αv integrin/PLP/neurotransmitter receptor protein complex forms that reduces binding to the extracellular matrix and enhances OPC migration. To assess the extent to which PLP was involved in the AMPA-stimulated migration, OPCs from the myelin-deficient (MD) rat, which has a PLP gene mutation, were analyzed. OPCs from the MD rat had a normal basal migration rate, but AMPA did not stimulate the migration of these cells, suggesting that the PLP/αv integrin complex was important for the AMPA-mediated induction. AMPA-induced modulation of OPC migration was abolished by pertussis toxin, although baseline migration was normal. Thus, G-protein-dependent signaling is crucial for AMPA-stimulated migration of OPCs but not for basal OPC migration. Other signaling pathways involved in this AMPA-stimulated OPC migration were also determined. These studies highlight novel signaling determinants of OPC migration and suggest that glutamate could play a pivotal role in regulating integrin-mediated OPC migration.
TL;DR: It is shown that VGLUT2 (Slc17a6) is required for life ex utero, and V GLUT2-mediated signaling as an obligatory component of the developing respiratory rhythm generator is identified.
Abstract: Glutamatergic excitatory neurotransmission is dependent on glutamate release from presynaptic vesicles loaded by three members of the solute carrier family, Slc17a6-8, which function as vesicular glutamate transporters (VGLUTs) Here, we show that VGLUT2 (Slc17a6) is required for life ex utero Vglut2 null mutant mice die immediately after birth because of the absence of respiratory behavior Investigations at embryonic stages revealed that neural circuits in the location of the pre-Botzinger (PBC) inspiratory rhythm generator failed to become active However, neurons with bursting pacemaker properties and anatomical integrity of the PBC area were preserved Vesicles at asymmetric synapses were fewer and malformed in the Vglut2 null mutant hindbrain, probably causing the complete disruption of AMPA/kainate receptor-mediated synaptic activity in mutant PBC cells The functional deficit results from an inability of PBC neurons to achieve synchronous activation In contrast to respiratory rhythm generation, the locomotor central pattern generator of Vglut2 null mutant mice displayed normal rhythmic and coordinated activity, suggesting differences in their operating principles Hence, the present study identifies VGLUT2-mediated signaling as an obligatory component of the developing respiratory rhythm generator
TL;DR: Preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies, and cannabinoids can act as an antioxidants in neuronal cultures.
Abstract: Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate The psychotropic cannabinoid receptor agonist delta 9-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action Glutamate toxicity can be reduced by antioxidants Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants As evidence that cannabinoids can act as an antioxidants in neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both alpha-tocopherol and ascorbate in protective capacity Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies
TL;DR: It has become clear that kainate receptors have a role in synaptic plasticity and that they might also have a fundamental role in epilepsy through the strategic control of network excitability.
TL;DR: Data demonstrate an area-specific deficit in gamma rhythmogenesis in animal models of psychiatric illness and suggest that loss, or reduction in function, of interneurons having a large NMDA receptor expression may underlie the network dysfunction that is seen.
Abstract: Psychiatric illnesses, particularly schizophrenia, are associated with disrupted markers for interneuronal function and interneuron-mediated brain rhythms such as gamma frequency oscillations. Here we investigate a possible link between these two observations in the entorhinal cortex and hippocampus by using a genetic and an acute model of psychiatric illness. Lysophosphatidic acid 1 receptor-deficient (LPA1-deficient) mice show psychomotor-gating deficits and neurochemical changes resembling those seen in postmortem schizophrenia studies. Similar deficits are seen acutely with antagonism of the NMDA subtype of glutamate receptor. Neither model induced any change in power or frequency of gamma rhythms generated by kainate in hippocampal slices. In contrast, a dramatic decrease in the power of gamma oscillations was seen in superficial, but not deep, medial entorhinal cortex layers in both models. Immunolabeling for GABA, parvalbumin, and calretinin in medial entorhinal cortex from LPA1-deficient mice showed an ∼40% reduction in total GABA- and parvalbumin-containing neurons, but no change in the number of calretinin-positive neurons. This deficit was specific for layer II (LII). No change in the number of neurons positive for these markers was seen in the hippocampus. Acute NMDA receptor blockade, which selectively reduces synaptic drive to LII entorhinal interneurons, also disrupted gamma rhythms in a similar manner in superficial entorhinal cortex, but not in hippocampus. These data demonstrate an area-specific deficit in gamma rhythmogenesis in animal models of psychiatric illness and suggest that loss, or reduction in function, of interneurons having a large NMDA receptor expression may underlie the network dysfunction that is seen.
TL;DR: It is suggested that conditioned influences on cocaine seeking depend on glutamate transmission and drugs with antagonist properties at various glutamate receptor subtypes could be useful in prevention of relapse induced by conditioned stimuli.
TL;DR: This novel SSP model was validated as a useful tool for screening neuroprotective strategies in vivo and Combination therapy optimized to limit neurotoxic effects of MK801 may be an effective neuroProtective approach in retinal degenerative disease.
Abstract: Glaucoma is a major cause of worldwide irreversible blindness. Vision loss is attributed to retinal ganglion cell (RGC) death—a hallmark of glaucoma. Glaucomatous RGC death has been shown to involve the apoptosis pathway,1,2 and RGC apoptosis is one of the earliest signs of the disease process in glaucoma.1,3 Excessive activation of glutamate receptors from the release of glutamate from injured RGCs is heavily implicated in this process.4 Glutamate is the principal excitatory neurotransmitter in the central nervous system (CNS) and the retina and has been found to be increased in glaucoma.4-6 Inhibition or blockade of glutamate activity by modulation of its receptors—in particular, modulating NMDA (N-methyl-d-aspartate)-type glutamate receptors— has been advocated as an important strategy for neuroprotection in glaucoma.
In the CNS and the retina, glutamate mediates excitatory neurotransmission via ion channel-associated (ionotropic) and G protein-coupled (metabotropic) receptors.7,8 The ionotropic (iGlu) receptors include NMDA, AMPA (α-animo-3-hydroxy-5-methyl-4-isoxazolepropionate), and KA (kainate) subtypes.7,8 A variety of NMDA antagonists, including memantine, MK801 (dizocilpine), dextromethorphan, flupirtine, and eliprodil, have been shown to ameliorate ischemia-induced insults to the retina. in vivo9-12 and in vitro,9,13 and to prevent or delay RGC death in several different models.9-11 NMDA receptors are thought to be heteromeric ion channel complexes that consist of two NR1 subunits and two NR2 subunits that can be either of the NR2A, -2B, -2C, or -2D type. In the rat retina, RGCs express both NR2A and -2B subunits, and it is thought that cells have a combination of different NMDA receptor types.14
Glutamate release has been implicated as a mechanism of RGC death in glaucoma,4,15-18 particularly with regard to secondary RGC degeneration.19-22 In addition, it has been heavily implicated in IOP-induced ischemia.23 It is very much the basis of several experimental glaucoma treatment studies, including those involving the NMDA antagonists MK801 in a rat ocular hypertensive model24 and memantine in rat and primate models,25-27 in which NMDA antagonists were shown to be neuroprotective. However, all these studies have relied on the quantification of RGC loss histologically and have not looked at the effects of agents on levels of RGC apoptosis.
G protein-coupled glutamate receptors are called metabotropic (mGlu) receptors because they couple to intracellular second messengers.28,29 Eight mGlu receptor subtypes have been identified so far, and these have been classified into three groups.28,29 The mGluR1 and mGluR5 are coupled positively to phospholipase C, and both are included in group I, whereas the others are coupled negatively to adenylate cyclase and belong to group II (mGluR2 and mGluR3) and group III (mGluR4, mGluR6, mGluR7, and mGluR8).28,29 mGluRs can modulate excitatory and inhibitory synaptic transmission through various transduction pathways. There is evidence that activation of group I mGluRs increases neuronal excitation, whereas that of group II and III mGluRs reduces synaptic transmission29; therefore, group I mGluR antagonists and group II and III mGluR agonists can be thought to be neuroprotective.29 Various studies have shown expression of mRNA and/or receptor proteins for all mGluRs in the retina.30-34 Furthermore, it has been recently shown that expression of some mGluRs is stimulated in ocular hypertension (OHT) rodent glaucoma models,35 although the effects of a combination of group I mGluR antagonists and group II and III mGluR agonists were not found to be protective of RGC death in an axotomy and NMDA excitotoxic model.36 Although group II mGluR agonists by themselves have been reported to be neuroprotective against apoptotic neuronal death,29 until now, specific and targeted modulation of group II mGluRs has not been assessed in retinal apoptosis or glaucoma models.
In this study, we sought to assess the effects of the broad-spectrum NMDA antagonist MK801 in our recently described model of staurosporine (SSP)-induced RGC apoptosis.3 To assess the relative contributions of NR2B-containing NMDA receptors in this apoptotic process, we also studied the effects of the NR2B-selective antagonist ifenprodil. As activation of group II mGluRs is neuroprotective through a different mechanism than that of NMDA antagonism, using this same model we investigated the actions of the group II agonist LY354740, and compared these effects with blockade of NMDA receptors. Finally, we assessed the effects of these agents in the OHT model of rodent glaucoma. All agents were investigated with our novel technique of in vivo RGC apoptosis imaging, which involves the correlation of the level of histologically confirmed RGC apoptosis to the effectiveness of neuroprotection.3
TL;DR: The data support the idea that the synthesis of estrogen can be rapidly regulated in the brain, thus producing rapid changes in local estrogen bioavailability that could rapidly modify brain function with a time course similar to what has previously been described for neurotransmitters and neuromodulators.
Abstract: Estrogens derived from the neural aromatization of testosterone play a key role in the activation of male sexual behavior in many vertebrates and have now been recognized to have rapid membrane effects on brain function. Such changes in aromatase activity and hence in local estrogen concentrations could rapidly modulate behavioral responses. We show here that there is a very rapid (within minutes) decrease in aromatase activity in quail hypothalamic explants exposed to treatments affecting intracellular Ca2+ concentrations, such as the addition of glutamate agonists (kainate, alpha-amino-3-hydroxymethyl-4-isoxazole propionic acid, and, to a much lesser extent, N-methyl-D-aspartate), but not of gamma-aminobutyric acid. The kainate effects, which reduce aromatase activity by 25-50%, are observed within 5 min, are completely blocked in explants exposed to specific kainate antagonists (6-cyano-7-nitroquinoxaline-2,3-dione disodium or 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium), and are also rapidly reversible when effectors are washed out. Together, these data support the idea that the synthesis of estrogen can be rapidly regulated in the brain, thus producing rapid changes in local estrogen bioavailability that could rapidly modify brain function with a time course similar to what has previously been described for neurotransmitters and neuromodulators.
TL;DR: New findings that shed light on the regulation of receptor cycling events and surface trafficking are focused on and the way that this might reshape the thinking about the specific regulation of receptors accumulation at synapses is considered.
Abstract: Glutamate receptor trafficking in and out of synapses is one of the core mechanisms for rapid changes in the number of functional receptors during synaptic plasticity. Recent data have shown that the fast gain and loss of receptors from synaptic sites are accounted for by endocytic/exocytic processes and by their lateral diffusion in the plane of the membrane. These events are interdependent and regulated by neuronal activity and interactions with scaffolding proteins. We review here the main cellular steps for AMPA and NMDA receptor synthesis, traffic within intracellular organelles, membrane exocytosis/endocytosis and surface trafficking. We focus on new findings that shed light on the regulation of receptor cycling events and surface trafficking and the way that this might reshape our thinking about the specific regulation of receptor accumulation at synapses.
TL;DR: In this paper, the N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors plays a key role in mediating at least some aspects of glutamate neurotoxicity.
TL;DR: During early development, transmission at CA3-CA1 synapses is regulated by a high-affinity, G protein-dependent kainate receptor (KAR), which is endogenously activated by ambient glutamate, which sets the dynamic properties of neonatal inputs to favor transmission during high frequency bursts of activity, typical for developing neuronal networks.
TL;DR: It is demonstrated that kynurenic acid (KYNA), an endogenous tryptophan metabolite, acts upon heterologous AMPA receptors via two distinct mechanisms, where low concentrations of KYNA facilitate AMPA receptor responses, whereas high concentrations ofKYNA competitively antagonize glutamate receptors.
TL;DR: Evidently LCM perturbs excitability in primary cortical cultures but does not appear to do so via a high-affinity interaction with an acknowledged recognition site on a target for existing antiepileptic drugs.
TL;DR: A large number of studies indicate the existence of presynaptic coincidence detection that is independent of NMDA receptors, suggesting that such mechanisms have a widespread role in plasticity.
TL;DR: Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.
Abstract: L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.
TL;DR: The data indicate short-term changes in neural plasticity, suggested by modulation of expression of key genes, and functional changes in striatal circuits, which might in turn trigger enduring changes responsible for the adult neurobehavioral profile.
TL;DR: Data suggest the existence of physically associated mu opioid and CB1 cannabinoid receptors, whereby activation of these receptors results in either a non-additive (glutamate release) or a synergistic (GABA release) effect.
TL;DR: The anatomical evidence supports numerous potential locations for receptor-neurotransmitter interactions, and raises important questions regarding mechanisms of activation and function of synaptic versus extrasynaptic receptors in the basal ganglia.
TL;DR: The results establish that kainate receptors have a role in recognition memory that is distinct from that of NMDA receptors, that there must be at least two independent underlying memory mechanisms in the infused region, and that perirhinal-dependent long-term recognition memory does not rely solely on processes used in NMDA-dependent LTP or LTD.
Abstract: To investigate the involvement of different types of glutamate receptors in recognition memory, selective antagonists of NMDA and kainate receptors were locally infused into the perirhinal cortex of the rat temporal lobe. Such infusion of a selective kainate receptor antagonist produced an unusual pattern of recognition memory impairment: amnesia after a short (20 min) but not a long (24 h) delay. In contrast, antagonism of perirhinal NMDA glutamate receptors by locally infused AP-5 (2-amino-5-phosphonopentanoic acid) impaired recognition memory after the long but not the short delay. For both drugs, impairment was found when the drug was present during acquisition but not when it was present during retrieval. Experiments in vitro indicate that selective antagonism of NMDA receptors containing NR2A subunits blocks perirhinal long-term potentiation (LTP), whereas antagonism of NMDA receptors containing NR2B subunits blocks long-term depression (LTD). However, recognition memory after a 24 h delay was impaired only when both an NR2A and an NR2B antagonist were infused together, not when either was infused separately. These results establish that kainate receptors have a role in recognition memory that is distinct from that of NMDA receptors, that there must be at least two independent underlying memory mechanisms in the infused region, that this region and no other is necessary for both short-term and long-term familiarity discrimination, and that perirhinal-dependent long-term recognition memory does not rely solely on processes used in NMDA-dependent LTP or LTD (although it might be independently supported by components of each type of process with one substituting for the other).
TL;DR: High-resolution crystal structures for the GluR5 ligand-binding core complex with UBP302 and UBP310, novel Glu R5-selective antagonists reveal the structural basis for the high selectivity for GLUR5 observed in radiolabel displacement assays and suggests that glutamate receptors are capable of much larger movements than previously thought.
Abstract: Glutamate receptor (GluR) ion channels mediate fast synaptic transmission in the mammalian CNS. Numerous crystallographic studies, the majority on the GluR2-subtype AMPA receptor, have revealed the structural basis for binding of subtype-specific agonists. In contrast, because there are far fewer antagonist-bound structures, the mechanisms for antagonist binding are much less well understood, particularly for kainate receptors that exist as multiple subtypes with a distinct biology encoded by the GluR5–7 , KA1 , and KA2 genes. We describe here high-resolution crystal structures for the GluR5 ligand-binding core complex with UBP302 and UBP310, novel GluR5-selective antagonists. The crystal structures reveal the structural basis for the high selectivity for GluR5 observed in radiolabel displacement assays for the isolated ligand binding cores of the GluR2, GluR5, and GluR6 subunits and during inhibition of glutamate-activated currents in studies on full-length ion channels. The antagonists bind via a novel mechanism and do not form direct contacts with the E723 side chain as occurs in all previously solved AMPA and kainate receptor agonist and antagonist complexes. This results from a hyperextension of the ligand binding core compared with previously solved structures. As a result, in dimer assemblies, there is a 22 A extension of the ion channel linkers in the transition from antagonist- to glutamate-bound forms. This large conformational change is substantially different from that described for AMPA receptors, was not possible to predict from previous work, and suggests that glutamate receptors are capable of much larger movements than previously thought.