Group II metabotropic glutamate receptors enhance NMDA receptor currents via a protein kinase C‐dependent mechanism in pyramidal neurones of rat prefrontal cortex

Tyszkiewicz, Joanna P.; Gu, Zhenglin; Wang, Xun; Cai, Xiang; Yan, Zhen

doi:10.1113/jphysiol.2003.056812

Cited by 67 publications

(73 citation statements)

References 67 publications

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“…Pyramidal neurons located in the intermediate and deep layers (III-VI) of the rat PFC were recorded. Recordings of whole-cell ion channel currents used standard voltage-clamp techniques (Yan et al, 1999;Wang et al, 2003;Tyszkiewicz et al, 2004). The internal solution consisted of the following (in mM): 180 N-methyl-D-glucamine, 40 HEPES, 4 MgCl 2 , 0.1 BAPTA, 12 phosphocreatine, 3 Na 2 ATP, 0.5 Na 2 GTP, and 0.1 leupeptin, pH 7.2-7.3 (265-270 mOsm/l).…”

Section: Methodsmentioning

confidence: 99%

Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism

Yuen¹

2005

Journal of Neuroscience

207

197

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The serotonin system and NMDA receptors (NMDARs) in prefrontal cortex (PFC) are both critically involved in the regulation of cognition and emotion under normal and pathological conditions; however, the interactions between them are essentially unknown. Here we show that serotonin, by activating 5-HT 1A receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT 1A receptors. This effect of 5-HT 1A receptors was blocked by agents that interfere with microtubule assembly, as well as by cellular knock-down of the kinesin motor protein KIF17 (kinesin superfamily member 17), which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Inhibition of either CaMKII (calcium/calmodulin-dependent kinase II) or MEK/ERK (mitogen-activated protein kinase kinase/extracellular signalregulated kinase) abolished the 5-HT 1A modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT 1A activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT 1A activation decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Together, these results suggest that serotonin suppresses NMDAR function through a mechanism dependent on microtubule/kinesinbased dendritic transport of NMDA receptors that is regulated by CaMKII and ERK signaling pathways. The 5-HT 1A -NMDAR interaction provides a potential mechanism underlying the role of serotonin in controlling emotional and cognitive processes subserved by PFC.

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Section: Methodsmentioning

confidence: 99%

Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism

Yuen¹

2005

Journal of Neuroscience

207

197

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“…The first indication of the therapeutic potential of this drug came from animal models showing that mGlu2/3 agonist reduces the overactivity produced by NMDA antagonist [50,51]. Such reduction might occur as a result of presynaptic reduction in excitation, but a recent report raises the possibility of postsynaptic enhancement of the NMDAR function [52].…”

Section: Nmda Hypofunctionmentioning

confidence: 99%

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Lisman

Coyle

Green

et al. 2008

Trends in Neurosciences

913

824

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Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

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“…We have recently reported that activation of group II mGluRs increases NMDAR currents in PFC pyramidal neurons via a PKC-dependent mechanism (Tyszkiewicz et al 2004). Considering that ␤-amyloid peptides impair the group I mGluR-mediated, PKC-dependent regulation of GABAergic transmission, we hypothesized that the group II mGluR-mediated, PKC-dependent regulation of NMDAR currents may also be impaired by A␤ exposure.…”

Section: ␤-Amyloid Peptides Impair the Group II Mglur-mediated Potentmentioning

confidence: 99%

“…For detecting activated PKC, a phospho-PKC (pan) antibody that recognizes PKC␣, ␤ I , ␤ II , ⑀, , and ␦ isoforms only when phosphorylated at a carboxyl-terminal residue homologous to Ser 660 of PKC␤ II was used in the Western blot analysis Tyszkiewicz et al 2004). After incubation, slices were transferred to boiling 1% SDS and homogenized immediately.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Whole cell recordings of currents in dissociated neurons employed standard voltage-clamp techniques (Tyszkiewicz et al 2004;Yan et al 1999). The internal solution consisted of (in mM) 180 N-methyl-D-glucamine (NMG), 40 HEPES, 4 MgCl 2 , 0.1 bis-(o-aminophenoxy)-N,N,NЈ,NЈ-tetraacetic acid (BAPTA), 12 phosphocreatine, 2 Na 2 ATP, 0.2 Na 3 GTP, and 0.1 leupeptin, pH ϭ 7.2-7.3, 265-270 mosM.…”

Section: Whole Cell Recordings In Acutely Dissociated Neuronsmentioning

confidence: 99%

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β-Amyloid Peptides Impair PKC-Dependent Functions of Metabotropic Glutamate Receptors in Prefrontal Cortical Neurons

Tyszkiewicz¹,

Yan²

2005

Journal of Neurophysiology

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Tyszkiewicz, Joanna P. and Zhen Yan. ␤-amyloid peptides impair PKC-dependent functions of metabotropic glutamate receptors in prefrontal cortical neurons. J Neurophysiol 93: 3102-3111, 2005. First published January 19, 2005 doi:10.1152/jn.00939.2004. The metabotropic glutamate receptors (mGluRs) have been implicated in cognition, memory, and some neurodegenerative disorders, including the Alzheimer's disease (AD). To understand how the dysfunction of mGluRs contributes to the pathophysiology of AD, we examined the ␤-amyloid peptide (A␤)-induced alterations in the physiological functions of mGluRs in prefrontal cortical pyramidal neurons. Two potential targets of mGluR signaling involved in cognition, the GABAergic system and the N-methyl-D-aspartate (NMDA) receptor, were examined. Activation of group I mGluRs with (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the spontaneous inhibitory postsynaptic current (sIPSC) amplitude, and this effect was protein kinase C (PKC) sensitive. Treatment with A␤ abolished the DHPG-induced enhancement of sIPSC amplitude. On the other hand, activation of group II mGluRs with (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) significantly increased the NMDA receptor (NMDAR)-mediated currents via a PKC-dependent mechanism, and A␤ treatment also diminished the APDC-induced potentiation of NMDAR currents. In A␤-treated slices, both DHPG and APDC failed to activate PKC. These results indicate that the mGluR regulation of GABA transmission and NMDAR currents is impaired by A␤ treatment probably due to the A␤-mediated interference of mGluR activation of PKC. This study provides a framework within which the role of mGluRs in normal cognitive functions and AD can be better understood.

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Group II metabotropic glutamate receptors enhance NMDA receptor currents via a protein kinase C‐dependent mechanism in pyramidal neurones of rat prefrontal cortex

Cited by 67 publications

References 67 publications

Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism

Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

β-Amyloid Peptides Impair PKC-Dependent Functions of Metabotropic Glutamate Receptors in Prefrontal Cortical Neurons

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