GLUTAMATE RELEASE AND UPTAKE AT CEREBELLAR SYNAPSES

  • Jahr, Craig, (PI)

Project: Research project

Description

DESCRIPTION: Extracellular levels of glutamate are controlled with great precision both temporally and spatially, achieving efficient and selective synaptic excitation and preventing neuronal death by excitotoxicity. On one hand, glutamate concentrations in the synaptic cleft must rise rapidly to millimolar concentrations to ensure activation of postsynaptic ionotropic receptors. On the other hand, sub-micromolar levels of glutamate, on average, must be maintained in the extracellular space to prevent cell death. These requirements are met by the explosive exocytotic release of glutamate and the high capacity and high affinity glutamate uptake system provided by the family of Na-dependent glutamate transporters. When these transporters are rendered ineffective, either pharmacologically, in transgenic mice, or by spontaneous mutation in humans (e.g., ALS), elevated tonic levels of glutamate and slowed clearance around synaptic release sites can result in seizures, enhanced susceptibility to ischemic insults, and neuronal and organismal death. The aim of this proposal is to determine how much glutamate escapes from the synaptic cleft following release, how far from the release site glutamate attains concentrations sufficient to activate receptors, how rapidly the uptake system sequesters glutamate, and how these processes are affected by physiological alterations in the amount of glutamate released including multivesicular release and variability in vesicular filling. We will use whole cell and outside-out patch clamp methods in acute rat cerebellar slices to address the consequences of ionotropic and metabotropic glutamate receptor activation inside and outside of the synaptic cleft, including receptors on neighboring glia and neurons.
StatusFinished
Effective start/end date5/18/001/31/16

Funding

  • National Institutes of Health: $279,350.00
  • National Institutes of Health: $385,000.00
  • National Institutes of Health: $226,500.00
  • National Institutes of Health: $325,085.00
  • National Institutes of Health: $264,875.00
  • National Institutes of Health: $333,507.00
  • National Institutes of Health: $279,350.00
  • National Institutes of Health: $226,500.00
  • National Institutes of Health: $336,875.00
  • National Institutes of Health: $336,875.00
  • National Institutes of Health: $264,875.00
  • National Institutes of Health: $226,500.00
  • National Institutes of Health: $272,786.00
  • National Institutes of Health: $221,400.00

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Synapses
Glutamic Acid
Neuroglia
Exocytosis
AMPA Receptors
Calcium
Presynaptic Receptors
Cerebellar Cortex
Synaptic Vesicles
Purkinje Cells
Calcium Channels
Neurosciences
Permeability
Physiological Phenomena
Ionotropic Glutamate Receptors
Amino Acid Transport System X-AG
Metabotropic Glutamate Receptors
Pharmacology
Photons
Brain

ASJC

  • Medicine(all)
  • Neuroscience(all)