14 results on '"Swanson, Geoffrey T."'
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2. Group II Metabotropic Glutamate Receptors (mGlu2 and mGlu3).
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., Johnson, Michael P., and Schoepp, Darryle D.
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The group II metabotropic glutamate (mGlu2 and mGlu3) receptors are among the minority of glutamate receptors that primarily inhibit synaptic transmission by coupling to Gio, inhibiting adenylate cyclase and potassium channels. Our understanding of their physiologic role has advanced considerably with the discovery of systemically active and selective agonists, antagonists, and, most recently, subtype-selective allosteric modulators. The mGlu2/3 agonists, such as LY354740 (and its prodrug LY544344), show activity in a number of preclinical models of anxiety, psychosis, and drug abuse and as neuroprotectants. The anxiolytic actions of group II agents have subsequently been confirmed in humans, and represent an exciting breakthrough in the glutamate field. Emerging preclinical results with mGlu2/3 antagonists and potentiators of the mGlu2 receptor indicate that, despite a presynaptic localization distal to the synaptic active zone, significant glutamatergic tone can occur under some physiologic conditions. This chapter describes some mGlu2/3-selective pharmacologic tools, briefly discusses the different synaptic and glial localizations, and notes how these unique receptors may regulate synaptic transmission. [ABSTRACT FROM AUTHOR]
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- 2008
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3. Metabotropic Glutamate Receptor Ligands as Novel Therapeutic Agents.
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., Brady, Ashley E., and Conn, P. Jeffrey
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Metabotropic glutamate receptors comprise a diverse family of G protein-coupled receptors that are critical for regulating normal neuronal function in the central nervous system (CNS). The heterogeneous distribution and diverse physiologic roles of the various mGluR subtypes make them highly attractive targets for the treatment of a number of neurologic and psychiatric disorders. The discovery of subtype-selective ligands for these receptors has provided the tools to support a number of preclinical studies, suggesting the tremendous therapeutic potential that lies in the ability selectively to modulate a specific mGluR subtype. In the last few years, a major milestone in the field was achieved with the first selective mGluR ligands entering into clinical development and demonstrating efficacy in the treatment of anxiety disorders. In addition to the discovery of selective, direct-acting mGluR ligands, a novel class of mGluR-selective ligands has recently emerged. These allosteric modulators, which act through nontraditional binding sites on the mGluRs, may exhibit even greater subtype selectivity than orthosteric ligands. Furthermore, because they modulate mGluRs in an activity-dependent manner, it is possible that allosteric activators of mGluRs will be less likely to induce adverse effects or promote receptor desensitization. This chapter summarizes the critical studies that have contributed to the validation of mGluRs as therapeutic targets for the treatment of a number of CNS disorders and describes progress thus far in identifying and developing novel mGluR subtype-selective compounds. [ABSTRACT FROM AUTHOR]
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- 2008
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4. Clinically Tolerated Strategies for NMDA Receptor Antagonism.
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., Huei-Sheng Vincent Chen, Dongxian Zhang, and Lipton, Stuart A.
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Many potentially neuroprotective drugs have failed in human clinical trials because of side effects that cause normal brain function to become compromised. An important example concerns antagonists of the N-methyl-D-aspartate type of glutamate receptor (NMDAR). Glutamate receptors are essential to the normal function of the central nervous system. However, their excessive activation by excitatory amino acids such as glutamate is thought to contribute to neuronal damage in many neurologic disorders ranging from acute hypoxic-ischemic brain injury to chronic neurodegenerative diseases such as Alzheimer disease, Parkinson disease, Huntington disease, HIV-associated dementia, multiple sclerosis, glaucoma, and amyotrophic lateral sclerosis. The dual role of NMDARs in particular for normal and abnormal functioning of the nervous system imposes important constraints on possible therapeutic strategies aimed at ameliorating neurologic diseases. Blockade of excessive NMDAR activity must therefore be achieved without interference with its normal function. In general, NMDAR antagonists can be categorized pharmacologically according to the site of action on the receptor-channel complex. These include drugs acting at the agonist (NMDA) or coagonist (glycine) sites, channel pore, and modulatory sites, such as the S-nitrosylation site, where nitric oxide (NO) reacts with critical cysteine thiol groups. Because glutamate is thought to be the major excitatory transmitter in the brain, generalized inhibition of a glutamate receptor subtype like the NMDAR causes side effects that clearly limit the potential for clinical applications. Both competitive NMDA and glycine antagonists, From: The Receptors: The Glutamate Receptors even though they are effective in preventing glutamate-mediated neurotoxicity, will cause generalized inhibition of NMDAR activities and thus have failed in many clinical trials. Open-channel block, a form of uncompetitive antagonism, is the most appealing strategy for therapeutic intervention during excessive NMDAR activation because this action of blockade; requires prior activation of the receptor. This property, in theory, leads to a higher degree of channel blockade in the presence of excessive levels of glutamate and little blockade at relatively lower levels, for example, during physiologic neurotransmission. As an alternative strategy, genetic manipulation of NR3 subunits can reduce glutamateinduced currents and Ca2+ influx through NMDARs without completely blocking their activation. Based on this molecular strategy of action, this chapter reviews the logical process that was applied over the last decade to develop memantine as the first clinically tolerated yet effective agent against NMDAR-mediated neurotoxicity. Phase 3 (final) clinical trials have shown that memantine is effective in treating moderateto- severe Alzheimer's disease while being well tolerated. Memantine is also in trials for additional neurologic disorders, including other forms of dementia, glaucoma, and severe neuropathic pain. In addition, taking advantage of memantine's preferential binding to open channels and the act that excessive NMDAR activity can be downregulated by S-nitrosylation, combinatorial drugs called NitroMemantine have recently been developed. These drugs use memantine as a homing signal to target NO to hyperactivated NMDARs to avoid systemic side effects of NO such as hypotension (low blood pressure). These second-generation memantine derivatives are designed as pathologically activated therapeutics, and in preliminary studies they appear to have even greater neuroprotective properties than memantine. [ABSTRACT FROM AUTHOR]
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- 2008
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5. Metabotropic Glutamate Receptor-Dependent Synaptic Plasticity.
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., Fitzjohn, Stephen M., and Bashir, Zafar I.
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Long-term potentiation (LTP) and long-term depression (LTD) are important forms of synaptic plasticity thought to underlie many brain processes such as those involved in brain development, memory, and drug addiction. The metabotropic glutamate receptors (mGluRs) are capable of inducing both LTP and LTD, and also of modulating the induction of plasticity initiated by other receptor systems. Although early work focused on the role of mGluRs in LTP, the precise nature of their involvement in LTP induction remains unclear. However, there is considerable evidence that activation of mGluRs can induce LTD in numerous brain regions. This chapter reviews the evidence for mGluR involvement in LTP induction and discusses the roles of mGluRs in LTD. In particular it describes the signaling pathways and expression mechanisms of two prominent forms of LTD—those seen in the CA1 region of the hippocampus and the cerebellum. [ABSTRACT FROM AUTHOR]
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- 2008
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6. Group III Metabotropic Glutamate Receptors (mGlu4, mGlu6, mGlu7, and mGlu8).
- Author
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., and Neugebauer, Volker
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G protein-coupled group III metabotropic glutamate receptors (mGluRs) include four subtypes that are negatively coupled to adenylyl cyclase (mGluRs 4, 7, and 8) or positively to a cGMP phosphodiesterase (mGluR6). Typically, they exert inhibitory influences on neuronal activity. This chapter reviews the characteristics of group III mGluRs and their normal functions and role in nervous system disorders. The therapeutic potential of group III mGluRs resides in their antiepileptic (mGluRs 4 and 7), neuroprotective (mGluRs 4, 7, and 8), anti-parkinsonian (mGluRs 4 and 7), anxiolytic (mGluR4), and analgesic effects. However, possible side effects may need to be considered because group III mGluRs can inhibit normal synaptic transmission and memory processes, and mGluR6 is important for visual transmission. This chapter emphasizes that the analysis of the role of individual group III mGluR subtypes is required to determine their potential therapeutic value. [ABSTRACT FROM AUTHOR]
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- 2008
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7. Positive Modulators of AMPA-Type Glutamate Receptors.
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., Lynch, Gary, and Gall, Christine M.
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Ampakines are small synthetic compounds that cross the blood-brain barrier and enhance fast excitatory synaptic responses mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. Their binding site has been identified and shown to be appropriately located for slowing receptor deactivation and desensitization, the two processes that terminate excitatory transmission. After reviewing these mechanisms, this paper takes up the question of why ampakines, although targeted at receptors found throughout the brain, produce surprisingly discrete behavioral effects. Three processes are hypothesized to be involved: (1) the facilitation of excitatory inputs to inhibitory interneurons balances the effects of ampakines on glutamatergic neurons; (2) the compounds have preferences for receptor subtypes and thus for particular brain regions; and (3) the potency of the ampakines scales positively with the complexity of brain networks. The discrete effects of the drugs raise the possibility of using them in the treatment of psychiatric disorders. Ampakines improve performance of complex behaviors in rodents and primates, accelerate learning across a diverse array of tests, and have positive effects in animal models of schizophrenia, attention deficit hyperactivity disorder (ADHD), and depression. Improved memory scores and a reduction in ADHD symptoms are also reported in studies with human subjects. It is hypothesized that these behavioral effects reflect facilitation of communication within cortex, a lowered threshold for the induction of long-term potentiation, and enhanced cortical regulation of lower brain systems. Finally, ampakines upregulate the production of brain-derived neurotrophic factor (BDNF). Experimental work prompted by this observation indicates that chronic ampakine treatments cause sizeable improvements in animal models of Parkinson disease, excitotoxic brain damage, and age-related losses of synaptic plasticity. [ABSTRACT FROM AUTHOR]
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- 2008
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8. The Structures of Metabotropic Glutamate Receptors.
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., Hampson, David R., Rose, Erin M., and Antflick, Jordan E.
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Interest in the structures of the metabotropic glutamate receptors continues to increase for a variety of reasons, including the fact that they are now established drug targets and are linked to a wide spectrum of physiologic processes both within and outside the central nervous system. This chapter summarizes our knowledge of the structures of the eight receptor subtypes, including the alternatively spliced forms, and the experimental approaches that have been used to study them. The large size and multiple domains of these proteins are conducive to further advances in the development of drugs for potential therapeutic use, and for basic research directed toward elucidating the intrinsic signaling mechanisms of these complex molecules. Increasingly detailed analyses of protein-protein interactions between the metabotropic glutamate receptors and other signaling molecules will also contribute to a deeper understanding of how this class of receptors and related G protein-coupled receptors, function at the molecular level within biologic membranes in vivo. [ABSTRACT FROM AUTHOR]
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- 2008
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9. Ionotropic Glutamate Receptors in Synaptic Plasticity.
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., Pelkey, Kenneth A., and McBain, Chris J.
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More than 30 years have elapsed since the publication of the first reports of long-term potentiation by Bliss and Lomo (1973) and Bliss and Gardner-Medwin (1973). These two reports ushered in an exciting new era in which measurable persistent changes in synaptic strength were posited as substrates for learning and memory. Since that time, the study of long-term mechanisms of synaptic plasticity have arguably been one of the most intensely and perhaps the most rewarding fields of the neurosciences, casting important light on the nature of synaptic transmission and the events associated with the strengthening or weakening of synapses. Indeed, although once principally studied at excitatory glutamatergic synapses within the hippocampus and cortical formations, mechanisms of synaptic plasticity are observed at a myriad of synaptic connections throughout the mammalian central nervous system. Moreover, although many of these synapses share common mechanisms of plasticity, the last decade has seen an explosion in our understanding of plasticities peculiar to one synapse or another. This chapter does not attempt to cover all of these divergent mechanisms but instead focuses on those mechanisms of long-term potentiation (LTP) and depression (LTD) most commonly found within the hippocampal formation. A large portion of this review covers N-methyl-\fontsize77\selectfont D-aspartate-receptor-dependent LTP and LTD, the two most commonly studied forms of cortical plasticity; however, it also addresses plasticity mechanisms at other hippocampal synapses that have not enjoyed the same intensity of investigation but are worthy of attention. [ABSTRACT FROM AUTHOR]
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- 2008
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10. Structural Correlates of Ionotropic Glutamate Receptor Function.
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., Kristensen, Anders S., Hansen, Kasper B., Wollmuth, Lonnie P., Egebjerg, Jan, and Traynelis, Stephen F.
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Recent structural and functional studies of ionotropic glutamate receptors (iGluRs) have begun to offer rare insight into the structure-function relationship for an integral membrane protein. In particular, advances in our understanding of iGluR structure are providing an opportunity to interpret functional work in terms of potential conformational changes. Moreover, working hypotheses derived from structural insight offer an opportunity to enrich and guide functional studies. This chapter summarizes knowledge of glutamate receptor structure, with an emphasis on how it has shaped our functional understanding of these receptors. [ABSTRACT FROM AUTHOR]
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- 2008
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11. Delta Receptors.
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., and Yuzaki, Michisuke
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No endogenous ligands have been identified for the delta subfamily of ionotropic glutamate receptors (GluRδ1 and GluRδ2). Nevertheless, GluRδ2 plays indispensable roles in cerebellar functions; mice that lack the GluRδ2 gene display ataxia and impaired motor-related learning tasks. Recent studies of mutant mice, such as lurcher, hotfoot, and GluRδ2- knockout mice, have provided clues to the structure and function of GluRδ2. In particular, morphologic and electrophysiologic analyses of hotfoot and GluRδ2-knockout mice have demonstrated a unique role of GluRδ2 in synapse formation and its maintenance. In addition, an antibody specific for GluRδ2′s extracellular N-terminal indicated its direct role in controlling cerebellar long-term depression. These results suggest that GluRδ2 regulates distinct s pathways involved in synapse formation and synaptic plasticity. [ABSTRACT FROM AUTHOR]
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- 2008
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12. Kainate Receptors.
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Neve, Kim A., Gereau, Robert W., Contractor, Anis, and Swanson, Geoffrey T.
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Kainate receptors are glutamate-gated ion channels whose functional roles in the brain have been only poorly understood until recently. A picture has developed over the last decade of kainate receptors as subtle actors in neurotransmission; they modulate excitatory and inhibitory transmission and neuronal excitability and generate small but prolonged depolarizations at a subset of postsynaptic sites. This chapter reviews a variety of aspects of kainate receptor function, including their structure, biophysical function, and activities in (and out) of synapses in the mammalian brain. [ABSTRACT FROM AUTHOR]
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- 2008
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13. NMDA Receptors.
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., Petralia, Ronald S., and Wenthold, Robert J.
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One of the major classes of ionotropic glutamate receptors is made up of the N-methyl-D-aspartate (NMDA) receptors, which require two agonists, glycine and glutamate, for activation and can pass calcium ions that may mediate synaptic and neuronal plasticity. They are formed from complexes made by various combinations of the subunits NR1 (with eight isoforms), NR2A-D, and NR3A-B and are found in most neurons of the brain and in various other cells. During development, generally NMDA receptors with NR2B, NR2D, and NR3A are abundant and decrease during maturation, whereas those with NR2A and NR2C increase. The function of NMDA receptors has been explored with a wide range of in vitro and in vivo studies, employing both recombinant gene constructs and native receptors. NMDA receptor subunits contain various motifs that control retention in the endoplasmic reticulum and trafficking through Golgi and other organelles to reach the cell membrane. Association of NMDA receptors with PDZ domain-containing proteins such as PSD-95 and SAP102 may be particularly important to trafficking and/or stabilization and function on the cell membrane. NMDA receptors on the cell membrane are sequestered mainly to the postsynaptic membrane of synapses, but some populations remain in extrasynaptic domains, especially those receptors that contain NR2B or NR2D. [ABSTRACT FROM AUTHOR]
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- 2008
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14. AMPA Receptors.
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Neve, Kim A., Gereau, Robert W., Swanson, Geoffrey T., Ashby, Michael C., Daw, Michael I., and Isaac, John T.R.
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α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMP ARs) are glutamate-gated ion channels. They are the neurotransmitter receptors that mediate the great majority of fast excitatory synaptic transmission in the mammalian brain and are found throughout the animal kingdom in organisms as diverse as rodents, honeybees, nematode worms, and humans. They are absolutely critical for brain function; for example, infusion of a selective AMPAR antagonist into the rat hippocampus in vivo completely silences excitatory transmission in that region (1). AMPARs are also required for adaptive changes in the brain, mediating the expression of forms of long-term and short-term synaptic plasticity that are believed to underlie learning and memory, development, and certain neurologic diseases (2-5). Thus, AMPARs play a central role in brain function, and consequently there is great interest in the development of novel therapies directed at modulating AMPAR function for treatment of neurologic disorders, such as Alzheimer disease and stroke. [ABSTRACT FROM AUTHOR]
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- 2008
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