Yanhua Huang | Iowa State University (original) (raw)

Papers by Yanhua Huang

Research paper thumbnail of H2Kb and H2Db regulate cerebellar long-term depression and limit motor learning

Proceedings of The National Academy of Sciences, 2009

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Research paper thumbnail of H2Kb and H2Db regulate cerebellar long-term depression and limit motor learning

Proceedings of The National Academy of Sciences, 2009

There are more than 50 class I MHC (MHCI) molecules in the mouse genome, some of which are now kn... more There are more than 50 class I MHC (MHCI) molecules in the mouse genome, some of which are now known to be expressed in neurons; however, the role of classical MHCI molecules in synaptic plasticity is unknown. We report that the classical MHCI molecules, H2-Kb and H2-Db, are co-expressed by Purkinje cells (PCs). In the cerebellum of mice deficient for both H2-Kb and H2-Db (KbDb-/-), there is a lower threshold for induction of long-term depression (LTD) at parallel fiber to PC synapses. This change may be a result of additional glutamate release observed at KbDb-/- CF to PC synapses, which are thought to “train” the cerebellar circuit. A behavioral correlate of cerebellar LTD is motor learning; acquisition and retention of a Rotarod behavioral task is significantly better in KbDb-/- mice than in WT cohorts. These physiological and behavioral phenotypes in KbDb-/- mice reveal a surprising role for classical MHCI molecules in synaptic plasticity and motor learning.

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Research paper thumbnail of Glutamate transporters bring competition to the synapse

Current Opinion in Neurobiology, 2004

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Research paper thumbnail of Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

Nature, 2004

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Research paper thumbnail of Synthesis and Characterization of 4Methoxy7-nitroindolinyl- d -aspartate, a Caged Compound for Selective Activation of Glutamate Transporters and N Methyl d -aspartate Receptors in Brain Tissue

Biochemistry, 2005

The D-isomer of aspartate is efficiently transported by high-affinity Na(+)/K(+)-dependent glutam... more The D-isomer of aspartate is efficiently transported by high-affinity Na(+)/K(+)-dependent glutamate transporters and is an effective ligand of N-methyl-d-aspartate (NMDA) receptors. To facilitate analysis of the regulation of these proteins in their native membranes, we synthesized a photolabile analogue of D-aspartate, 4-methoxy-7-nitroindolinyl-D-aspartate (MNI-D-aspartate). This compound was photolyzed with a quantum efficiency of 0.09 at pH 7.4. Photorelease of d-aspartate in acute hippocampal slices through brief (1 ms) UV laser illumination of MNI-d-aspartate triggered rapidly activating currents in astrocytes that were inhibited by the glutamate transporter antagonist DL-threo-beta-benzyloxyaspartic acid (TBOA), indicating that they resulted from electrogenic uptake of D-aspartate. These transporter currents exhibited a distinct tail component that was approximately 2% of the peak current, which may result from the release of K(+) into the extracellular space during counter transport. MNI-D-aspartate was neither an agonist nor an antagonist of glutamate transporters at concentrations up to 500 muM and was stable in aqueous solution for several days. Glutamate transporter currents were also elicited in Bergmann glial cells and Purkinje neurons of the cerebellum in response to photolysis of MNI-D-aspartate, indicating that this compound can be used for monitoring the occupancy and regulation of glutamate transporters in different brain regions. Photorelease of D-aspartate did not activate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors or metabotropic glutamate receptors (mGluRs) in neurons, but resulted in the selective, but transient, activation of NMDA receptors in hippocampal pyramidal neurons; MNI-D-aspartate was not an antagonist of NMDA receptors. These results indicate that MNI-D-aspartate also may be useful for studying the regulation of NMDA receptors at excitatory synapses.

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Research paper thumbnail of beta-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

Nature, 2005

Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of syn... more Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many β-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. β-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the β-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.

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Research paper thumbnail of Climbing Fiber Activation of EAAT4 Transporters and Kainate Receptors in Cerebellar Purkinje Cells

Journal of Neuroscience, 2004

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Research paper thumbnail of b-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

Nature

Page 1. ..... b-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expr... more Page 1. ..... b-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression Jeffrey D. Rothstein1,2, Sarjubhai Patel1, Melissa R. Regan1, Christine Haenggeli1, Yanhua ...

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Research paper thumbnail of Astrocyte Glutamate Transporters Regulate Metabotropic Glutamate Receptor-Mediated Excitation of Hippocampal Interneurons

Journal of Neuroscience, 2004

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Research paper thumbnail of Ncm- d-aspartate: A novel caged d-aspartate suitable for activation of glutamate transporters and N-methyl- d-aspartate (NMDA) receptors in brain tissue

Neuropharmacology, 2005

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Research paper thumbnail of In Vivo Cocaine Experience Generates Silent Synapses

Neuron, 2009

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Research paper thumbnail of Cocaine-induced homeostatic regulation and dysregulation of nucleus accumbens neurons

Behavioural Brain Research, 2011

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Research paper thumbnail of Sleep loss alters synaptic and intrinsic neuronal properties in mouse prefrontal cortex

Brain Research, 2011

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Research paper thumbnail of H2Kb and H2Db regulate cerebellar long-term depression and limit motor learning

Proceedings of The National Academy of Sciences, 2009

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Research paper thumbnail of H2Kb and H2Db regulate cerebellar long-term depression and limit motor learning

Proceedings of The National Academy of Sciences, 2009

There are more than 50 class I MHC (MHCI) molecules in the mouse genome, some of which are now kn... more There are more than 50 class I MHC (MHCI) molecules in the mouse genome, some of which are now known to be expressed in neurons; however, the role of classical MHCI molecules in synaptic plasticity is unknown. We report that the classical MHCI molecules, H2-Kb and H2-Db, are co-expressed by Purkinje cells (PCs). In the cerebellum of mice deficient for both H2-Kb and H2-Db (KbDb-/-), there is a lower threshold for induction of long-term depression (LTD) at parallel fiber to PC synapses. This change may be a result of additional glutamate release observed at KbDb-/- CF to PC synapses, which are thought to “train” the cerebellar circuit. A behavioral correlate of cerebellar LTD is motor learning; acquisition and retention of a Rotarod behavioral task is significantly better in KbDb-/- mice than in WT cohorts. These physiological and behavioral phenotypes in KbDb-/- mice reveal a surprising role for classical MHCI molecules in synaptic plasticity and motor learning.

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Research paper thumbnail of Glutamate transporters bring competition to the synapse

Current Opinion in Neurobiology, 2004

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Research paper thumbnail of Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

Nature, 2004

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Research paper thumbnail of Synthesis and Characterization of 4Methoxy7-nitroindolinyl- d -aspartate, a Caged Compound for Selective Activation of Glutamate Transporters and N Methyl d -aspartate Receptors in Brain Tissue

Biochemistry, 2005

The D-isomer of aspartate is efficiently transported by high-affinity Na(+)/K(+)-dependent glutam... more The D-isomer of aspartate is efficiently transported by high-affinity Na(+)/K(+)-dependent glutamate transporters and is an effective ligand of N-methyl-d-aspartate (NMDA) receptors. To facilitate analysis of the regulation of these proteins in their native membranes, we synthesized a photolabile analogue of D-aspartate, 4-methoxy-7-nitroindolinyl-D-aspartate (MNI-D-aspartate). This compound was photolyzed with a quantum efficiency of 0.09 at pH 7.4. Photorelease of d-aspartate in acute hippocampal slices through brief (1 ms) UV laser illumination of MNI-d-aspartate triggered rapidly activating currents in astrocytes that were inhibited by the glutamate transporter antagonist DL-threo-beta-benzyloxyaspartic acid (TBOA), indicating that they resulted from electrogenic uptake of D-aspartate. These transporter currents exhibited a distinct tail component that was approximately 2% of the peak current, which may result from the release of K(+) into the extracellular space during counter transport. MNI-D-aspartate was neither an agonist nor an antagonist of glutamate transporters at concentrations up to 500 muM and was stable in aqueous solution for several days. Glutamate transporter currents were also elicited in Bergmann glial cells and Purkinje neurons of the cerebellum in response to photolysis of MNI-D-aspartate, indicating that this compound can be used for monitoring the occupancy and regulation of glutamate transporters in different brain regions. Photorelease of D-aspartate did not activate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors or metabotropic glutamate receptors (mGluRs) in neurons, but resulted in the selective, but transient, activation of NMDA receptors in hippocampal pyramidal neurons; MNI-D-aspartate was not an antagonist of NMDA receptors. These results indicate that MNI-D-aspartate also may be useful for studying the regulation of NMDA receptors at excitatory synapses.

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Research paper thumbnail of beta-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

Nature, 2005

Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of syn... more Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many β-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. β-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the β-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Climbing Fiber Activation of EAAT4 Transporters and Kainate Receptors in Cerebellar Purkinje Cells

Journal of Neuroscience, 2004

Bookmarks Related papers MentionsView impact

Research paper thumbnail of b-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

Nature

Page 1. ..... b-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expr... more Page 1. ..... b-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression Jeffrey D. Rothstein1,2, Sarjubhai Patel1, Melissa R. Regan1, Christine Haenggeli1, Yanhua ...

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Research paper thumbnail of Astrocyte Glutamate Transporters Regulate Metabotropic Glutamate Receptor-Mediated Excitation of Hippocampal Interneurons

Journal of Neuroscience, 2004

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Ncm- d-aspartate: A novel caged d-aspartate suitable for activation of glutamate transporters and N-methyl- d-aspartate (NMDA) receptors in brain tissue

Neuropharmacology, 2005

Bookmarks Related papers MentionsView impact

Research paper thumbnail of In Vivo Cocaine Experience Generates Silent Synapses

Neuron, 2009

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Cocaine-induced homeostatic regulation and dysregulation of nucleus accumbens neurons

Behavioural Brain Research, 2011

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Sleep loss alters synaptic and intrinsic neuronal properties in mouse prefrontal cortex

Brain Research, 2011

Bookmarks Related papers MentionsView impact