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.
Department of Physiology, Graduate School of Medicine and Dentistry, Okayama University, Shikata, Okayama, Japan. shiri-ns@umin.ac.jp
Sheng-Tian
ST
Li
Masayuki
M
Matsushita
Akiyoshi
A
Moriwaki
Yasunori
Y
Saheki
Yun-Fei
YF
Lu
Kazuhito
K
Tomizawa
Hai-Yan
HY
Wu
Hiroaki
H
Terada
Hideki
H
Matsui
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