Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice
- 213 Downloads
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.
KeywordsGlutamate transporters gp120 HIV-1 Striatum Cognitive deficits
All authors approved the final version of this article. The authors would like to thank L. Perez for his excellent technical assistance. This work was supported in part by National Institutes of Health Grants SNRP-U54N54301, 2R25GM061151 and NIGMS 1P20GM103642.
Compliance with ethical standards
All protocols were approved by the Institutional Animal Care and Use Committee at the UPR-SOM and in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (2012) and AVMA Guidelines for the Euthanasia of Animals (2013).
Conflict of interest
The authors declare that there is no conflict of interests.
- AVMA (2013) AVMA guidelines for the euthanasia of animals, 2013 edn. American Veterinary Medical Association, Schaumburg, ILGoogle Scholar
- Benos DJ, Hahn BH, Bubien JK, Ghosh SK, Mashburn NA, Chaikin MA, Shaw GM, Benveniste EN (1994) Envelope glycoprotein gp120 of human immunodeficiency virus type 1 alters ion transport in astrocytes: implications for AIDS dementia complex. Proc Natl Acad Sci U S A 91:494–498CrossRefPubMedPubMedCentralGoogle Scholar
- Holden CP, Haughey NJ, Nath A, Geiger JD (1999) Role of Na+/H+ exchangers, excitatory amino acid receptors and voltage-operated Ca2+ channels in human immunodeficiency virus type 1 gp120-mediated increases in intracellular Ca2+ in human neurons and astrocytes. Neuroscience 91:1369–1378CrossRefPubMedGoogle Scholar
- Matsugami TR, Tanemura K, Mieda M, Nakatomi R, Yamada K, Kondo T, Ogawa M, Obata K, Watanabe M, Hashikawa T, Tanaka K (2006) From the cover: indispensability of the glutamate transporters GLAST and GLT1 to brain development. Proc Natl Acad Sci U S A 103:12161–12166CrossRefPubMedPubMedCentralGoogle Scholar
- Moore DJ, Masliah E, Rippeth JD, Gonzalez R, Carey CL, Cherner M, Ellis RJ, Achim CL, Marcotte TD, Heaton RK, Grant I, Group HNRC (2006) Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment. AIDS 20:879–887. doi: 10.1097/01.aids.0000218552.69834.00 CrossRefPubMedGoogle Scholar
- National Research Council (2012) Guide for the care and use of laboratory animals. National Academy Press, Washington, D.C.Google Scholar
- Paxinos G, Franklin K (2012) The mouse brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego, CAGoogle Scholar