The Experts below are selected from a list of 11862 Experts worldwide ranked by ideXlab platform
Ehud Y Isacoff - One of the best experts on this subject based on the ideXlab platform.
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a red shifted fast relaxing azobenzene photoswitch for visible light control of an Ionotropic Glutamate Receptor
Journal of the American Chemical Society, 2013Co-Authors: Michael A Kienzler, Dirk Trauner, Andreas Reiner, Eric P Trautman, Ehud Y IsacoffAbstract:The use of azobenzene photoswitches has become a dependable method for rapid and exact modulation of biological processes and material science systems. The requirement of ultraviolet light for azobenzene isomerization is not ideal for biological systems due to poor tissue penetration and potentially damaging effects. While modified azobenzene cores with a red-shifted cis-to-trans isomerization have been previously described, they have not yet been incorporated into a powerful method to control protein function: the photoswitchable tethered ligand (PTL) approach. We report the synthesis and characterization of a red-shifted PTL, L-MAG0460, for the light-gated Ionotropic Glutamate Receptor LiGluR. In cultured mammalian cells, the LiGluR+L-MAG0460 system is activated rapidly by illumination with 400–520 nm light to generate a large ionic current. The current rapidly turns off in the dark as the PTL relaxes thermally back to the trans configuration. The visible light excitation and single-wavelength behavior ...
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A modern Ionotropic Glutamate Receptor with a K + selectivity signature sequence
Nature communications, 2011Co-Authors: H. Janovjak, G. Sandoz, Ehud Y IsacoffAbstract:Glutamate is the major excitatory neurotransmitter in the mammalian nervous system. Here, a Glutamate Receptor is reported that has properties intermediate to those of bacterial and eukaryotic Glutamate-gated ion channels, suggesting a link in the evolution of Ionotropic Glutamate Receptors.
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a modern Ionotropic Glutamate Receptor with a k selectivity signature sequence
Nature Communications, 2011Co-Authors: Ehud Y Isacoff, H. Janovjak, G. SandozAbstract:Glutamate is the major excitatory neurotransmitter in the mammalian nervous system. Here, a Glutamate Receptor is reported that has properties intermediate to those of bacterial and eukaryotic Glutamate-gated ion channels, suggesting a link in the evolution of Ionotropic Glutamate Receptors.
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mechanisms of photoswitch conjugation and light activation of an Ionotropic Glutamate Receptor
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Pau Gorostiza, Matthew Volgraf, Ehud Y Isacoff, Dirk Trauner, Rika Numano, Stephanie SzobotaAbstract:The analysis of cell signaling requires the rapid and selective manipulation of protein function. We have synthesized photoswitches that covalently modify target proteins and reversibly present and withdraw a ligand from its binding site due to photoisomerization of an azobenzene linker. We describe here the properties of a Glutamate photoswitch that controls an ion channel in cells. Affinity labeling and geometric constraints ensure that the photoswitch controls only the targeted channel, and enables spatial patterns of light to favor labeling in one location over another. Photoswitching to the activating state places a tethered Glutamate at a high (millimolar) effective local concentration near the binding site. The fraction of active channels can be set in an analog manner by altering the photostationary state with different wavelengths. The bistable photoswitch can be turned on with millisecond-long pulses at one wavelength, remain on in the dark for minutes, and turned off with millisecond long pulses at the other wavelength, yielding sustained activation with minimal irradiation. The system provides rapid, reversible remote control of protein function that is selective without orthogonal chemistry.
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allosteric control of an Ionotropic Glutamate Receptor with an optical switch
Nature Chemical Biology, 2006Co-Authors: Matthew Volgraf, Pau Gorostiza, Richard H. Kramer, Ehud Y Isacoff, Dirk Trauner, Rika NumanoAbstract:The precise regulation of protein activity is fundamental to life. The allosteric control of an active site by a remote regulatory binding site is a mechanism of regulation found across protein classes, from enzymes to motors to signaling proteins. We describe a general approach for manipulating allosteric control using synthetic optical switches. Our strategy is exemplified by a ligand-gated ion channel of central importance in neuroscience, the Ionotropic Glutamate Receptor (iGluR). Using structure-based design, we have modified its ubiquitous clamshell-type ligand-binding domain to develop a light-activated channel, which we call LiGluR. An agonist is covalently tethered to the protein through an azobenzene moiety, which functions as the optical switch. The agonist is reversibly presented to the binding site upon photoisomerization, initiating clamshell domain closure and concomitant channel gating. Photoswitching occurs on a millisecond timescale, with channel conductances that reflect the photostationary state of the azobenzene at a given wavelength. Our device has potential uses not only in biology but also in bioelectronics and nanotechnology.
James H Meadorwoodruff - One of the best experts on this subject based on the ideXlab platform.
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ontogeny of Ionotropic Glutamate Receptor subunit expression in the rat hippocampus
Developmental Brain Research, 2002Co-Authors: Laura M Ritter, Delia M Vazquez, James H MeadorwoodruffAbstract:Abstract The Ionotropic Glutamate Receptors play key roles in multiple developmental mechanisms, including regulation of neuronal migration and differentiation, and synaptic organization. In this study, we investigated the developmental expression of these Glutamate Receptors in the postnatal rat hippocampus. We examined the transcripts encoding the subunits composing the N-methyl- d -aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate (KA) subtypes of Glutamate Receptors by in situ hybridization at multiple time points from postnatal day (PND) 1 to PND 35. In the case of the AMPA Receptor, gluR1 expression did not change over this time period, while gluR2, gluR3, and gluR4 did. These three subunits each underwent a transient period of increased expression at either PND 7 or PND 18. All five of the kainate Receptor subunits changed during this time, all starting at relatively high levels of expression that declined by PND 35. Similar to most of the AMPA subunits, all of the kainate subunits had transient periods of significantly increased expression. The NMDA Receptors all changed during over time as well, and each had a period of increased expression. The periods of transiently increased expression of all of these subunits coincide with known periods of plasticity and other critical times in development. These results suggest the different Glutamate Receptor subtypes may be critical at specific times during postnatal brain development.
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ontogeny of Ionotropic Glutamate Receptor expression in human fetal brain
Developmental Brain Research, 2001Co-Authors: Laura M Ritter, Alan S Unis, James H MeadorwoodruffAbstract:Abstract Glutamate Receptors have multiple roles in the central nervous system. Recent evidence suggests that the iontropic Glutamate Receptors are critical during brain development, particularly for corticogenesis, neuronal migration, and synaptogenesis. In this study, we examined subunit mRNA expression and binding sites of the NMDA, AMPA, and kainate Receptors from gestational weeks 8–20 in human fetal brain. Expression of Glutamate Receptors was high during several periods in these brains. Different levels of expression of each NMDA, AMPA, and kainate Receptor subunit transcripts were present during development, with a greater abundance of NR1, NR2B, NR2D, GluR7, and KA1 mRNA at most gestational ages. Binding sites for NMDA, AMPA, and kainate Receptors were all detected, but each had a unique pattern of expression. These results demonstrate that Glutamate Receptors are expressed early in human brain development, and undergo complex changes over time consistent with their role in normal development.
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Ionotropic Glutamate Receptor binding and subunit mrna expression in thalamic nuclei in schizophrenia
American Journal of Psychiatry, 2000Co-Authors: Hisham M Ibrahim, Alan J. Hogg, Daniel J Healy, Vahram Haroutunian, Kenneth L Davis, James H MeadorwoodruffAbstract:OBJECTIVE: Both thalamic and Glutamatergic dysfunction have been implicated in the pathophysiology of schizophrenia. The authors examined Ionotropic Glutamate Receptor expression in postmortem samples from patients with schizophrenia and comparison subjects, using the hypothesis that Glutamate Receptor expression differs in limbic nuclei of the thalamus in schizophrenia. METHOD: N-Methyl-d-aspartate (NMDA), AMPA, and kainate Receptor expression was determined in six thalamic nuclei from 12 subjects with DSM-III-R diagnoses of schizophrenia and eight psychiatrically normal individuals. The authors used in situ hybridization to determine NMDAR1, NMDAR2A–NMDAR2D, gluR1–gluR7, KA1, and KA2 subunit mRNA levels and Receptor autoradiography to determine binding to Glutamate binding sites of the three Receptor subtypes and to the glycine, polyamine, and ion channel binding sites of the NMDA Receptor. RESULTS: Glutamate Receptor expression was lower at both transcriptional (NMDAR1, NMDAR2B, NMDAR2C, gluR1, gluR3, ...
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Ionotropic Glutamate Receptor modulation of 5 ht6 and 5 ht7 mrna expression in rat brain
Neuropsychopharmacology, 1999Co-Authors: Daniel J Healy, James H MeadorwoodruffAbstract:The novel serotonin Receptor subtypes, 5-HT6 and 5-HT7, are located in limbic regions and have nanomolar affinities for atypical antipsychotics. These factors have led some to speculate about the involvement of 5-HT6 and 5-HT7 Receptors in schizophrenia. However, relatively little is known about these Receptor subtypes, including the regulation of their expression in limbic regions. In particular, the regulation of extracellular serotonin levels in the striatum and hippocampal formation by Glutamate Receptors led us to examine the effects of systemic Ionotropic Glutamate Receptor modulator treatment on 5-HT6 and 5-HT7 Receptor expression in these regions. MK-801 treatment induced a dose-dependent decrease in striatal 5-HT6 Receptor mRNA levels; similarly, both aniracetam and NBQX treatments also led to decreases in striatal 5-HT6 Receptor mRNA levels. Hippocampal 5-HT6 and 5-HT7 Receptor expression were not dramatically affected by any of the treatments. To our knowledge, this is the first demonstration of the regulation of striatal 5-HT6 Receptor mRNA expression, and provides neurochemical anatomical evidence for the interaction of serotonergic and Glutamatergic systems. Furthermore, although these two neurotransmitter systems are separately implicated in schizophrenia, the Glutamatergic regulation of the expression of a Receptor subtype associated with schizophrenia suggests that alterations in serotonin Receptor expression in schizophrenia may result, in part, from altered Glutamatergic activity.
James H. Meador-woodruff - One of the best experts on this subject based on the ideXlab platform.
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Striatal Ionotropic Glutamate Receptor expression in schizophrenia, bipolar disorder, and major depressive disorder.
Brain research bulletin, 2001Co-Authors: James H. Meador-woodruff, Alan J. Hogg, Robert E. SmithAbstract:Abnormalities of the Ionotropic Glutamate Receptors (N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid [AMPA], and kainate) have been reported in the brain in schizophrenia, although in complex, region-specific patterns. While limbic cortex and medial temporal lobe structures have been most often studied in psychiatric illnesses, Glutamate Receptors are expressed in other brain regions associated with limbic circuitry, especially the striatum. In this study, we have determined striatal Ionotropic Glutamate Receptor expression in brains from persons with schizophrenia, bipolar disorder, major depression, and a comparison group, using samples from the Stanley Foundation Neuropathology Consortium. We have determined the expression of these Receptors at multiple levels of gene expression by using both in situ hybridization and Receptor autoradiography. The expression of nearly all of these molecules was not different in these psychiatric conditions. The only significant changes noted were NR2D and gluR1 transcripts, and [(3)H]AMPA binding. This is the first comprehensive study of striatal Ionotropic Glutamate Receptor expression in schizophrenia and affective disorders, and suggests that there are minimal changes in these Receptors in this region of the brain in these illnesses.
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Ionotropic Glutamate Receptor modulation preferentially affects NMDA Receptor expression in rat hippocampus.
Synapse (New York N.Y.), 2000Co-Authors: Daniel J Healy, James H. Meador-woodruffAbstract:Electrophysiological data suggest that alterations in the function of one Glutamate Receptor subtype may affect the function of other subtypes. Further, previous studies have demonstrated that NMDA Receptor antagonists affect NMDA and kainate Receptor expression in rat hippocampus. In order to address the mutual regulation of NMDA, AMPA, and kainate Receptor expression in rat hippocampus, we conducted two experiments examining the effects of NMDA and non-NMDA Glutamate Receptor modulators on NMDA, AMPA, and kainate Receptor expression using in situ hybridization and Receptor autoradiography. NMDA Receptor expression was preferentially affected by systemic treatments, as all drugs significantly altered [(3)H]MK-801 binding, and several drugs increased [(3)H]ifenprodil binding. GYKI52466 and aniracetam treatments resulted in changes in both [(3)H]ifenprodil binding and NR2B mRNA levels, consistent with the association of this subunit and binding site in vitro. There were more modest effects on AMPA and kainate Receptor expression, even by direct antagonists. Together, these data suggest that Ionotropic Glutamate Receptors interact at the level of expression. These data also suggest that drug regimens targeting one Ionotropic Glutamate Receptor subtype may indirectly affect other subtypes, potentially producing unwanted side effects.
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Ionotropic Glutamate Receptor Modulation of 5-HT_6 and 5-HT_7 mRNA Expression in Rat Brain
Neuropsychopharmacology, 1999Co-Authors: Daniel J Healy, James H. Meador-woodruffAbstract:The novel serotonin Receptor subtypes, 5-HT_6 and 5-HT_7, are located in limbic regions and have nanomolar affinities for atypical antipsychotics. These factors have led some to speculate about the involvement of 5-HT_6 and 5-HT_7 Receptors in schizophrenia. However, relatively little is known about these Receptor subtypes, including the regulation of their expression in limbic regions. In particular, the regulation of extracellular serotonin levels in the striatum and hippocampal formation by Glutamate Receptors led us to examine the effects of systemic Ionotropic Glutamate Receptor modulator treatment on 5-HT_6 and 5-HT_7 Receptor expression in these regions. MK-801 treatment induced a dose-dependent decrease in striatal 5-HT_6 Receptor mRNA levels; similarly, both aniracetam and NBQX treatments also led to decreases in striatal 5-HT_6 Receptor mRNA levels. Hippocampal 5-HT_6 and 5-HT_7 Receptor expression were not dramatically affected by any of the treatments. To our knowledge, this is the first demonstration of the regulation of striatal 5-HT_6 Receptor mRNA expression, and provides neurochemical anatomical evidence for the interaction of serotonergic and Glutamatergic systems. Furthermore, although these two neurotransmitter systems are separately implicated in schizophrenia, the Glutamatergic regulation of the expression of a Receptor subtype associated with schizophrenia suggests that alterations in serotonin Receptor expression in schizophrenia may result, in part, from altered Glutamatergic activity.
Nicholas C. Spitzer - One of the best experts on this subject based on the ideXlab platform.
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mechanism for neurotransmitter Receptor matching
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Dena R Hammondweinberger, Alex Glavisbloom, Yunxin Wang, Nicholas C. SpitzerAbstract:Synaptic communication requires the expression of functional postsynaptic Receptors that match the presynaptically released neurotransmitter. The ability of neurons to switch the transmitter they release is increasingly well documented, and these switches require changes in the postsynaptic Receptor population. Although the activity-dependent molecular mechanism of neurotransmitter switching is increasingly well understood, the basis of specification of postsynaptic neurotransmitter Receptors matching the newly expressed transmitter is unknown. Using a functional assay, we show that sustained application of Glutamate to embryonic vertebrate skeletal muscle cells cultured before innervation is necessary and sufficient to up-regulate Ionotropic Glutamate Receptors from a pool of different Receptors expressed at low levels. Up-regulation of these Ionotropic Receptors is independent of signaling by metabotropic Glutamate Receptors. Both imaging of Glutamate-induced calcium elevations and Western blots reveal Ionotropic Glutamate Receptor expression prior to immunocytochemical detection. Sustained application of Glutamate to skeletal myotomes in vivo is necessary and sufficient for up-regulation of membrane expression of the GluN1 NMDA Receptor subunit. Pharmacological antagonists and morpholinos implicate p38 and Jun kinases and MEF2C in the signal cascade leading to Ionotropic Glutamate Receptor expression. The results suggest a mechanism by which neuronal release of transmitter up-regulates postsynaptic expression of appropriate transmitter Receptors following neurotransmitter switching and may contribute to the proper expression of Receptors at the time of initial innervation.
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mechanism for neurotransmitter Receptor matching
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Dena R Hammondweinberger, Alex Glavisbloom, Yunxin Wang, Nicholas C. SpitzerAbstract:Synaptic communication requires the expression of functional postsynaptic Receptors that match the presynaptically released neurotransmitter. The ability of neurons to switch the transmitter they release is increasingly well documented, and these switches require changes in the postsynaptic Receptor population. Although the activity-dependent molecular mechanism of neurotransmitter switching is increasingly well understood, the basis of specification of postsynaptic neurotransmitter Receptors matching the newly expressed transmitter is unknown. Using a functional assay, we show that sustained application of Glutamate to embryonic vertebrate skeletal muscle cells cultured before innervation is necessary and sufficient to up-regulate Ionotropic Glutamate Receptors from a pool of different Receptors expressed at low levels. Up-regulation of these Ionotropic Receptors is independent of signaling by metabotropic Glutamate Receptors. Both imaging of Glutamate-induced calcium elevations and Western blots reveal Ionotropic Glutamate Receptor expression prior to immunocytochemical detection. Sustained application of Glutamate to skeletal myotomes in vivo is necessary and sufficient for up-regulation of membrane expression of the GluN1 NMDA Receptor subunit. Pharmacological antagonists and morpholinos implicate p38 and Jun kinases and MEF2C in the signal cascade leading to Ionotropic Glutamate Receptor expression. The results suggest a mechanism by which neuronal release of transmitter up-regulates postsynaptic expression of appropriate transmitter Receptors following neurotransmitter switching and may contribute to the proper expression of Receptors at the time of initial innervation.
Daniel J Healy - One of the best experts on this subject based on the ideXlab platform.
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Ionotropic Glutamate Receptor modulation preferentially affects NMDA Receptor expression in rat hippocampus.
Synapse (New York N.Y.), 2000Co-Authors: Daniel J Healy, James H. Meador-woodruffAbstract:Electrophysiological data suggest that alterations in the function of one Glutamate Receptor subtype may affect the function of other subtypes. Further, previous studies have demonstrated that NMDA Receptor antagonists affect NMDA and kainate Receptor expression in rat hippocampus. In order to address the mutual regulation of NMDA, AMPA, and kainate Receptor expression in rat hippocampus, we conducted two experiments examining the effects of NMDA and non-NMDA Glutamate Receptor modulators on NMDA, AMPA, and kainate Receptor expression using in situ hybridization and Receptor autoradiography. NMDA Receptor expression was preferentially affected by systemic treatments, as all drugs significantly altered [(3)H]MK-801 binding, and several drugs increased [(3)H]ifenprodil binding. GYKI52466 and aniracetam treatments resulted in changes in both [(3)H]ifenprodil binding and NR2B mRNA levels, consistent with the association of this subunit and binding site in vitro. There were more modest effects on AMPA and kainate Receptor expression, even by direct antagonists. Together, these data suggest that Ionotropic Glutamate Receptors interact at the level of expression. These data also suggest that drug regimens targeting one Ionotropic Glutamate Receptor subtype may indirectly affect other subtypes, potentially producing unwanted side effects.
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Ionotropic Glutamate Receptor binding and subunit mrna expression in thalamic nuclei in schizophrenia
American Journal of Psychiatry, 2000Co-Authors: Hisham M Ibrahim, Alan J. Hogg, Daniel J Healy, Vahram Haroutunian, Kenneth L Davis, James H MeadorwoodruffAbstract:OBJECTIVE: Both thalamic and Glutamatergic dysfunction have been implicated in the pathophysiology of schizophrenia. The authors examined Ionotropic Glutamate Receptor expression in postmortem samples from patients with schizophrenia and comparison subjects, using the hypothesis that Glutamate Receptor expression differs in limbic nuclei of the thalamus in schizophrenia. METHOD: N-Methyl-d-aspartate (NMDA), AMPA, and kainate Receptor expression was determined in six thalamic nuclei from 12 subjects with DSM-III-R diagnoses of schizophrenia and eight psychiatrically normal individuals. The authors used in situ hybridization to determine NMDAR1, NMDAR2A–NMDAR2D, gluR1–gluR7, KA1, and KA2 subunit mRNA levels and Receptor autoradiography to determine binding to Glutamate binding sites of the three Receptor subtypes and to the glycine, polyamine, and ion channel binding sites of the NMDA Receptor. RESULTS: Glutamate Receptor expression was lower at both transcriptional (NMDAR1, NMDAR2B, NMDAR2C, gluR1, gluR3, ...
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Ionotropic Glutamate Receptor Modulation of 5-HT_6 and 5-HT_7 mRNA Expression in Rat Brain
Neuropsychopharmacology, 1999Co-Authors: Daniel J Healy, James H. Meador-woodruffAbstract:The novel serotonin Receptor subtypes, 5-HT_6 and 5-HT_7, are located in limbic regions and have nanomolar affinities for atypical antipsychotics. These factors have led some to speculate about the involvement of 5-HT_6 and 5-HT_7 Receptors in schizophrenia. However, relatively little is known about these Receptor subtypes, including the regulation of their expression in limbic regions. In particular, the regulation of extracellular serotonin levels in the striatum and hippocampal formation by Glutamate Receptors led us to examine the effects of systemic Ionotropic Glutamate Receptor modulator treatment on 5-HT_6 and 5-HT_7 Receptor expression in these regions. MK-801 treatment induced a dose-dependent decrease in striatal 5-HT_6 Receptor mRNA levels; similarly, both aniracetam and NBQX treatments also led to decreases in striatal 5-HT_6 Receptor mRNA levels. Hippocampal 5-HT_6 and 5-HT_7 Receptor expression were not dramatically affected by any of the treatments. To our knowledge, this is the first demonstration of the regulation of striatal 5-HT_6 Receptor mRNA expression, and provides neurochemical anatomical evidence for the interaction of serotonergic and Glutamatergic systems. Furthermore, although these two neurotransmitter systems are separately implicated in schizophrenia, the Glutamatergic regulation of the expression of a Receptor subtype associated with schizophrenia suggests that alterations in serotonin Receptor expression in schizophrenia may result, in part, from altered Glutamatergic activity.
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Ionotropic Glutamate Receptor modulation of 5 ht6 and 5 ht7 mrna expression in rat brain
Neuropsychopharmacology, 1999Co-Authors: Daniel J Healy, James H MeadorwoodruffAbstract:The novel serotonin Receptor subtypes, 5-HT6 and 5-HT7, are located in limbic regions and have nanomolar affinities for atypical antipsychotics. These factors have led some to speculate about the involvement of 5-HT6 and 5-HT7 Receptors in schizophrenia. However, relatively little is known about these Receptor subtypes, including the regulation of their expression in limbic regions. In particular, the regulation of extracellular serotonin levels in the striatum and hippocampal formation by Glutamate Receptors led us to examine the effects of systemic Ionotropic Glutamate Receptor modulator treatment on 5-HT6 and 5-HT7 Receptor expression in these regions. MK-801 treatment induced a dose-dependent decrease in striatal 5-HT6 Receptor mRNA levels; similarly, both aniracetam and NBQX treatments also led to decreases in striatal 5-HT6 Receptor mRNA levels. Hippocampal 5-HT6 and 5-HT7 Receptor expression were not dramatically affected by any of the treatments. To our knowledge, this is the first demonstration of the regulation of striatal 5-HT6 Receptor mRNA expression, and provides neurochemical anatomical evidence for the interaction of serotonergic and Glutamatergic systems. Furthermore, although these two neurotransmitter systems are separately implicated in schizophrenia, the Glutamatergic regulation of the expression of a Receptor subtype associated with schizophrenia suggests that alterations in serotonin Receptor expression in schizophrenia may result, in part, from altered Glutamatergic activity.
