title: 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: Department of Medical Sciences, Neuroscience Center, University of Ferrara, National Institute of Neuroscience, Italy. silvia.zucchini@unife.it
authors: Silvia
authors: S
authors: Zucchini
authors: Anna
authors: A
authors: Pittaluga
authors: Egidio
authors: E
authors: Brocca-Cofano
authors: Maria
authors: M
authors: Summa
authors: Marina
authors: M
authors: Fabris
authors: Rita
authors: R
authors: De Michele
authors: Angela
authors: A
authors: Bonaccorsi
authors: Graziella
authors: G
authors: Busatto
authors: Giuseppe
authors: G
authors: Barbanti-Brodano
authors: Giuseppe
authors: G
authors: Altavilla
authors: Gianluca
authors: G
authors: Verlengia
authors: Pierangelo
authors: P
authors: Cifelli
authors: Alfredo
authors: A
authors: Corallini
authors: Antonella
authors: A
authors: Caputo
authors: Michele
authors: M
authors: Simonato
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015696:Gene Products, tat / Q000494:pharmacology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009422:Nervous System Diseases / Q000473:pathology* / Q000821:virology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D018709:Statistics, Nonparametric; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D015696:Gene Products, tat; D018377:Neurotransmitter Agents; D050496:Vesicular Glutamate Transport Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D007608:Kainic Acid