Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice

J Neurovirol. 2016 Jun;22(3):358-65. doi: 10.1007/s13365-015-0403-6. Epub 2015 Nov 13.


The mechanisms leading to the neurocognitive deficits in humans with immunodeficiency virus type 1 (HIV-1) are not well resolved. A number of cell culture models have demonstrated that the HIV-envelope glycoprotein 120 (gp120) decreases the reuptake of glutamate, which is necessary for learning, memory, and synaptic plasticity. However, the impact of brain HIV-1 gp120 on glutamate uptake systems in vivo remains unknown. Notably, alterations in brain glutamate uptake systems are implicated in a number of neurodegenerative and neurocognitive disorders. We characterized the kinetic properties of system XAG (sodium-dependent) and systems xc- (sodium-independent) [3H]-L-glutamate uptake in the striatum and hippocampus of HIV-1 gp120 transgenic mice, an established model of HIV neuropathology. We determined the kinetic constant Vmax (maximal velocity) and Km (affinity) of both systems XAG and xc- using subcellular preparations derived from neurons and glial cells. We show significant (30-35 %) reductions in the Vmax of systems XAG and xc- in both neuronal and glial preparations derived from the striatum, but not from the hippocampus of gp120 mice relative to wild-type (WT) controls. Moreover, immunoblot analysis showed that the protein expression of glutamate transporter subtype-1 (GLT-1), the predominant brain glutamate transporter, was significantly reduced in the striatum but not in the hippocampus of gp120 mice. These extensive and region-specific deficits of glutamate uptake likely contribute to the development and/or severity of HIV-associated neurocognitive disorders. Understanding the role of striatal glutamate uptake systems in HIV-1 gp120 may advance the development of new therapeutic strategies to prevent neuronal damage and improve cognitive function in HIV patients.

Keywords: Cognitive deficits; Glutamate transporters; HIV-1; Striatum; gp120.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cognitive Dysfunction / complications
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / metabolism*
  • Cognitive Dysfunction / virology
  • Corpus Striatum / metabolism*
  • Corpus Striatum / virology
  • Disease Models, Animal
  • Excitatory Amino Acid Transporter 2 / deficiency
  • Excitatory Amino Acid Transporter 2 / genetics*
  • Glutamic Acid / metabolism
  • HIV Envelope Protein gp120 / genetics*
  • HIV Envelope Protein gp120 / metabolism
  • HIV Infections / complications
  • HIV Infections / genetics
  • HIV Infections / metabolism*
  • HIV Infections / virology
  • HIV-1 / pathogenicity*
  • HIV-1 / physiology
  • Hippocampus / metabolism
  • Hippocampus / virology
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Neuroglia / metabolism*
  • Neuroglia / virology
  • Neurons / metabolism
  • Neurons / virology
  • Organ Specificity
  • Synapses / metabolism
  • Synapses / virology
  • Transgenes


  • Excitatory Amino Acid Transporter 2
  • HIV Envelope Protein gp120
  • Glutamic Acid