HIV-1 Tat inhibits long-term potentiation and attenuates spatial learning [corrected].
Although memory deficits have been clearly documented in patients with human immunodeficiency virus type-1 (HIV-1) infection, the physiological basis of this dysfunction is poorly understood. We focused on Tat, a viral protein released from HIV-1-infected cells and investigated its effect on spatial learning in adult mice. An intracerebroventricular injection of Tat leads to attenuation of spatial learning accompanied by suppression of long-term potentiation (LTP), the cellular basis of spatial learning, in hippocampal cornu ammonis 1 pyramidal neurons. Tat facilitates extrasynaptic but not synaptic N-methyl-D-aspartate (NMDA) receptor activity. Taken together, these data provide strong evidence that the Tat pathway underlies the development of memory dysfunction in patients with HIV-1 infection and suggest a causal relationship between Tat, the facilitation of extrasynaptic NMDA receptor activity, inhibition of LTP, and attenuation of spatial learning.
Li
Sheng-Tian
ST
Department of Physiology, Graduate School of Medicine and Dentistry, Okayama University, Shikata, Okayama, Japan. shiri-ns@umin.ac.jp
Matsushita
Masayuki
M
Moriwaki
Akiyoshi
A
Saheki
Yasunori
Y
Lu
Yun-Fei
YF
Tomizawa
Kazuhito
K
Wu
Hai-Yan
HY
Terada
Hiroaki
H
Matsui
Hideki
H
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001640:Bicuculline / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000528:radiation effects; D018756:GABA Antagonists / Q000494:pharmacology; D015696:Gene Products, tat / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry* / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D066298:In Vitro Techniques; D007276:Injections, Intraventricular / Q000379:methods; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D018613:Microscopy, Confocal; D016202:N-Methylaspartate / Q000494:pharmacology; D009431:Neural Conduction / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010455:Peptides / Q000494:pharmacology; D013037:Spatial Behavior / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D054322:tat Gene Products, Human Immunodeficiency Virus
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D015696:Gene Products, tat; D010455:Peptides; D054322:tat Gene Products, Human Immunodeficiency Virus; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D002118:Calcium; D001640:Bicuculline