title: Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice.
abstract: 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.
authors.affiliation: Department of Anatomy and Neurobiology, University of Puerto Rico, Medical Sciences Campus, Office #A-527, San Juan, 00936, Puerto Rico. Roberto.Melendez2@upr.edu.
authors.forename: Roberto I
authors.initials: RI
authors.lastname: Melendez
authors.affiliation: Department of Anatomy and Neurobiology, University of Puerto Rico, Medical Sciences Campus, Office #A-527, San Juan, 00936, Puerto Rico.
authors.forename: Cristina
authors.initials: C
authors.lastname: Roman
authors.affiliation: Department of Biology, University of Puerto Rico, Rio Piedras, PR, 00936, USA.
authors.forename: Coral M
authors.initials: CM
authors.lastname: Capo-Velez
authors.affiliation: Department of Biology, University of Puerto Rico, Rio Piedras, PR, 00936, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Lasalde-Dominicci
mesh_terms: D000818:Animals; D060825:Cognitive Dysfunction / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D003342:Corpus Striatum / Q000378:metabolism* / Q000821:virology; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000172:deficiency / Q000235:genetics*; D018698:Glutamic Acid / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism* / Q000821:virology; D009474:Neurons / Q000378:metabolism / Q000821:virology; D009928:Organ Specificity; D013569:Synapses / Q000378:metabolism / Q000821:virology; D019076:Transgenes
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D015699:HIV Envelope Protein gp120; D018698:Glutamic Acid
keywords: Cognitive deficits; Glutamate transporters; HIV-1; Striatum; gp120