Presynaptic regulation of astroglial excitatory neurotransmitter transporter GLT1

Neuron. 2009 Mar 26;61(6):880-94. doi: 10.1016/j.neuron.2009.02.010.

Abstract

The neuron-astrocyte synaptic complex is a fundamental operational unit of the nervous system. Astroglia regulate synaptic glutamate, via neurotransmitter transport by GLT1/EAAT2. Astroglial mechanisms underlying this essential neuron-glial communication are not known. We now show that presynaptic terminals regulate astroglial synaptic functions, GLT1/EAAT2, via kappa B-motif binding phosphoprotein (KBBP), the mouse homolog of human heterogeneous nuclear ribonucleoprotein K (hnRNP K), which binds the GLT1/EAAT2 promoter. Neuron-stimulated KBBP is required for GLT1/EAAT2 transcriptional activation and is responsible for astroglial alterations in neural injury. Denervation of neuron-astrocyte signaling by corticospinal tract transection, ricin-induced motor neuron death, or neurodegeneration in amyotrophic lateral sclerosis all result in reduced astroglial KBBP expression and transcriptional dysfunction of astroglial transporter expression. Presynaptic elements dynamically coordinate normal astroglial function and also provide a fundamental signaling mechanism by which altered neuronal function and injury leads to dysregulated astroglia in CNS disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Astrocytes / cytology*
  • Cerebral Cortex / cytology
  • Coculture Techniques / methods
  • Dose-Response Relationship, Drug
  • Electrophoretic Mobility Shift Assay / methods
  • Embryo, Mammalian
  • Excitatory Amino Acid Agents / pharmacology
  • Excitatory Amino Acid Transporter 2 / genetics
  • Excitatory Amino Acid Transporter 2 / metabolism*
  • Green Fluorescent Proteins / genetics
  • Humans
  • Kainic Acid / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microfluidic Analytical Techniques / methods
  • Mutagenesis
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Neurons / physiology
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / physiology*
  • Pyramidal Tracts / metabolism
  • Pyramidal Tracts / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channel Blockers / pharmacology
  • Spinal Cord Injuries / pathology
  • Superoxide Dismutase / genetics
  • Synapses / drug effects
  • Synapses / physiology*
  • Tetrodotoxin / pharmacology
  • Transfection / methods
  • Up-Regulation / physiology

Substances

  • Excitatory Amino Acid Agents
  • Excitatory Amino Acid Transporter 2
  • NF-kappa B
  • Sodium Channel Blockers
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Tetrodotoxin
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Kainic Acid