Kainate Receptors on Hippocampal Interneurons

Summary

Principal Investigator: MATTHEW E FRERKING
Abstract: Inhibitory interneurons in the hippocampus regulate pyramidal cells and prevent hyperexcitability that leads to epileptiform activity. Glutamatergic transmission onto interneurons activates these cells to drive these functions. Recently, it has been shown that hippocampal interneurons express the kainate subtype of ionotropic glutamate receptor, and these kainate receptors (KARs) are synaptically activated. Postsynaptic KARs on interneurons contribute to the excitatory postsynaptic potential (EPSP). KARs on interneurons also depress the release of GABA from interneurons onto pyramidal cells, although the mechanisms underlying this effect remain unclear. These two actions suggest that interneuronal KARs play a major role in the control of inhibitory activity and output in the hippocampus, and possibly represent a therapeutic target to limit hyperexcitability during epilepsy. However, at present it is not possible to critically evaluate this possibility, because insufficient information is available about the functions of interneuronal KARs, the mechanisms by which these functions can be regulated, or the mechanisms by which KARs regulate GABA release. This proposal will seek to address these gaps in our understanding of KARs on interneurons. Using whole-cell patch clamp techniques, the activity of KARs on interneurons will be recorded and manipulated using pharmacological tools. Three specific aims will be addressed. (1) Functions for postsynaptic KARs will be identified, by testing four hypotheses: (a) that KARs are calcium-permeable and can initiate calcium-dependent signaling; (b) that KARs are segregated to different afferent pathways than AMPA receptors; (c) that KARs allow interneurons to perform temporal integration at low afferent firing frequencies; and (d) that these three functions are differentially distributed among different interneuronal subclasses. (2) Mechanisms of regulating the KAR-mediated EPSP will be identified, by testing two hypotheses: (a) that the KAR-mediated EPSP is regulated by continuous receptor delivery to, and removal from, the synapse; and (b) that the KAR-mediated EPSP is subject to activity-dependent synaptic plasticity. (3) Mechanisms underlying the presynaptic actions of interneuronal KARs will be identified, by testing two hypotheses: (a) that glutamate can activate presynaptic KARs that directly regulate GABA release; and (b) that the depression induced by KARs is an indirect consequence of interneuronal spiking. These experiments will provide information about the role of interneuronal KARs in the hippocampus, and provide a rational basis for future experiments to assess the possibility of manipulating these KARs to control hyperexcitability.
Funding Period: 2003-06-01 - 2009-04-30
more information: NIH RePORT

Top Publications

  1. pmc Spike timing in CA3 pyramidal cells during behavior: implications for synaptic transmission
    M Frerking
    Neurological Sciences Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
    J Neurophysiol 94:1528-40. 2005
  2. pmc Functional consequences of presynaptic inhibition during behaviorally relevant activity
    M Frerking
    Neurological Sciences Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
    J Neurophysiol 96:2139-43. 2006
  3. ncbi Presynaptic inhibition by kainate receptors converges mechanistically with presynaptic inhibition by adenosine and GABAB receptors
    Dara Partovi
    Neurological Sciences Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA
    Neuropharmacology 51:1030-7. 2006
  4. ncbi FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice
    Vivianne Deng
    Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA
    Hum Mol Genet 16:640-50. 2007
  5. pmc Spine expansion and stabilization associated with long-term potentiation
    Yunlei Yang
    Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA
    J Neurosci 28:5740-51. 2008
  6. pmc Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation
    Yunlei Yang
    Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA
    Proc Natl Acad Sci U S A 105:11388-93. 2008
  7. pmc Subunit-dependent postsynaptic expression of kainate receptors on hippocampal interneurons in area CA1
    Joyce Wondolowski
    Department of Behavioral Neuroscience and Neuroscience Graduate Program, Oregon Health and Science University, Beaverton, Oregon 97006, USA
    J Neurosci 29:563-74. 2009

Scientific Experts

  • MATTHEW E FRERKING
  • Yunlei Yang
  • Joyce Wondolowski
  • Xiao bin Wang
  • Qiang Zhou
  • Vivianne Deng
  • Dara Partovi
  • Sergio R Ojeda
  • Sarojini Budden
  • Fatima Banine
  • Patricia Ohliger
  • Jonathan Pevsner
  • Larry S Sherman
  • Valerie Matagne
  • Gregory A Dissen

Detail Information

Publications7

  1. pmc Spike timing in CA3 pyramidal cells during behavior: implications for synaptic transmission
    M Frerking
    Neurological Sciences Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
    J Neurophysiol 94:1528-40. 2005
    ..This study indicates that spike timing is regulated over long time scales and suggests that slow synaptic mechanisms could play a substantial role in information processing in the CNS...
  2. pmc Functional consequences of presynaptic inhibition during behaviorally relevant activity
    M Frerking
    Neurological Sciences Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
    J Neurophysiol 96:2139-43. 2006
    ..Our analysis suggests that presynaptic inhibition also enhances the importance of integrative inputs that respond to many behavioral cues during the task at the expense of specific inputs that respond to only a few of these cues...
  3. ncbi Presynaptic inhibition by kainate receptors converges mechanistically with presynaptic inhibition by adenosine and GABAB receptors
    Dara Partovi
    Neurological Sciences Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA
    Neuropharmacology 51:1030-7. 2006
    ..These results suggest that ATPA and domoate inhibit glutamate release through mechanisms that converge with those of classical metabotropic receptor agonists, although they do so through different receptors...
  4. ncbi FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice
    Vivianne Deng
    Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA
    Hum Mol Genet 16:640-50. 2007
    ..FXYD1 is therefore a MeCP2 target gene whose de-repression may directly contribute to RTT neuronal pathogenesis...
  5. pmc Spine expansion and stabilization associated with long-term potentiation
    Yunlei Yang
    Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA
    J Neurosci 28:5740-51. 2008
    ..These results indicate that the initial expression of LTP and spine expansion is dissociable, but there is a high degree of mechanistic overlap between the stabilization of structural plasticity and LTP...
  6. pmc Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation
    Yunlei Yang
    Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA
    Proc Natl Acad Sci U S A 105:11388-93. 2008
    ..These results demonstrate that AMPARs are rapidly trafficked to perisynaptic sites shortly after LTP induction and suggest that the delivery and maintenance of perisynaptic AMPARs may serve as a checkpoint in the expression of LTP...
  7. pmc Subunit-dependent postsynaptic expression of kainate receptors on hippocampal interneurons in area CA1
    Joyce Wondolowski
    Department of Behavioral Neuroscience and Neuroscience Graduate Program, Oregon Health and Science University, Beaverton, Oregon 97006, USA
    J Neurosci 29:563-74. 2009
    ..GluR5-containing KARs on interneurons in stratum oriens do not contribute substantially to the EPSC. We conclude that KARs are localized to synapses by cell type-, synapse-, and subunit-selective mechanisms...