Increased excitability in tat-transgenic mice: role of tat in HIV-related neurological disorders.

Abstract

HIV-1 associated neurocognitive disorders (HAND) are a major complication of HIV-1 infection. The mechanism(s) underlying HAND are not completely understood but, based on in vitro studies, the HIV-1 Tat protein may play an important role. In this study, the effect of prolonged exposure to endogenously produced Tat in the brain was investigated using a tat-transgenic (TT) mouse model constitutively expressing the HIV-1 tat gene. We found that stimulus-evoked glutamate exocytosis in the hippocampus and cortex was significantly increased in TT as compared with wild-type control (CC) mice, while GABA exocytosis was unchanged in the hippocampus and decreased in the cortex. This suggests that Tat generates a latent hyper-excitability state, which favors the detrimental effects of neurotoxic and/or excitotoxic agents. To challenge this idea, TT mice were tested for susceptibility to kainate-induced seizures and neurodegeneration, and found to exhibit significantly greater responses to the convulsant agent than CC mice. These results support the concept that constitutive expression of tat in the brain generates a latent excitatory state, which may increase the negative effects of damaging insults. These events may play a key role in the development of HAND.

• Authors: Silvia Zucchini, Anna Pittaluga, Egidio Brocca-Cofano, Maria Summa, Marina Fabris, Rita De Michele, Angela Bonaccorsi, Graziella Busatto, Giuseppe Barbanti-Brodano, Giuseppe Altavilla, Gianluca Verlengia, Pierangelo Cifelli, Alfredo Corallini, Antonella Caputo, Michele Simonato
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 55 Pg. 110-9 (Jul 2013) ISSN: 1095-953X [Electronic] United States
• PMID: 23454193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Gene Products, tat
• Neurotransmitter Agents
• Vesicular Glutamate Transport Proteins
• tat Gene Products, Human Immunodeficiency Virus
• Kainic Acid

Topics

• Analysis of Variance
• Animals
• Brain (drug effects, metabolism, pathology, virology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gene Products, tat (pharmacology)
• Kainic Acid (toxicity)
• Male
• Mice
• Mice, Transgenic
• Nervous System Diseases (pathology, virology)
• Neurotransmitter Agents (metabolism)
• Seizures (chemically induced, physiopathology)
• Statistics, Nonparametric
• Vesicular Glutamate Transport Proteins (metabolism)
• tat Gene Products, Human Immunodeficiency Virus (genetics, metabolism)