Disruptions in the regulation of extracellular glutamate by neurons and glia in the rat striatum two days after diffuse brain injury

Jason M. Hinzman, Theresa Currier Thomas, Jorge E. Quintero, Greg A. Gerhardt, Jonathan Lifshitz

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Disrupted regulation of extracellular glutamate in the central nervous system contributes to and can exacerbate the acute pathophysiology of traumatic brain injury (TBI). Previously, we reported increased extracellular glutamate in the striatum of anesthetized rats 2 days after diffuse brain injury. To determine the mechanism(s) responsible for increased extracellular glutamate, we used enzyme-based microelectrode arrays (MEAs) coupled with specific pharmacological agents targeted at in vivo neuronal and glial regulation of extracellular glutamate. After TBI, extracellular glutamate was significantly increased in the striatum by (∼90%) averaging 4.1±0.6μM compared with sham 2.2±0.4μM. Calcium-dependent neuronal glutamate release, investigated by local application of an N-type calcium channel blocker, was no longer a significant source of extracellular glutamate after TBI, compared with sham. In brain-injured animals, inhibition of glutamate uptake with local application of an excitatory amino acid transporter inhibitor produced significantly greater increase in glutamate spillover (∼ 65%) from the synapses compared with sham. Furthermore, glutamate clearance measured by locally applying glutamate into the extracellular space revealed significant reductions in glutamate clearance parameters in brain-injured animals compared with sham. Taken together, these data indicate that disruptions in calcium-mediated glutamate release and glial regulation of extracellular glutamate contribute to increased extracellular glutamate in the striatum 2 days after diffuse brain injury. Overall, these data suggest that therapeutic strategies used to regulate glutamate release and uptake may improve excitatory circuit function and, possibly, outcomes following TBI.

Original languageEnglish (US)
Pages (from-to)1197-1208
Number of pages12
JournalJournal of Neurotrauma
Volume29
Issue number6
DOIs
StatePublished - Apr 10 2012
Externally publishedYes

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Neuroglia
Glutamic Acid
Neurons
Diffuse Brain Injury
N-Type Calcium Channels
Calcium
Amino Acid Transport Systems
Excitatory Amino Acids
Brain
Calcium Channel Blockers
Extracellular Space
Microelectrodes
Synapses
Central Nervous System

Keywords

  • ω-conotoxin
  • (S)-4-carboxyphenylglycine
  • Dl-threo-β-benzyloxyaspartate
  • LY 379268

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Disruptions in the regulation of extracellular glutamate by neurons and glia in the rat striatum two days after diffuse brain injury. / Hinzman, Jason M.; Thomas, Theresa Currier; Quintero, Jorge E.; Gerhardt, Greg A.; Lifshitz, Jonathan.

In: Journal of Neurotrauma, Vol. 29, No. 6, 10.04.2012, p. 1197-1208.

Research output: Contribution to journalArticle

Hinzman, Jason M. ; Thomas, Theresa Currier ; Quintero, Jorge E. ; Gerhardt, Greg A. ; Lifshitz, Jonathan. / Disruptions in the regulation of extracellular glutamate by neurons and glia in the rat striatum two days after diffuse brain injury. In: Journal of Neurotrauma. 2012 ; Vol. 29, No. 6. pp. 1197-1208.
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