title: Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice.
abstract: BACKGROUND
  Human immunodeficiency virus (HIV) associated neurocognitive disorders (HAND), including memory dysfunction, continue to be a major clinical manifestation of HIV type-1 infection. Viral proteins released by infected glia are thought to be the principal triggers of inflammation and bystander neuronal injury and death, thereby driving key symptomatology of HAND.
  
  
  METHODS
  We used a glial fibrillary acidic protein-driven, doxycycline-inducible HIV type-1 transactivator of transcription (Tat) transgenic mouse model and examined structure-function relationships in hippocampal pyramidal cornu ammonis 1 (CA1) neurons using morphologic, electrophysiological (long-term potentiation [LTP]), and behavioral (Morris water maze, fear-conditioning) approaches.
  
  
  RESULTS
  Tat induction caused a variety of different inclusions in astrocytes characteristic of lysosomes, autophagic vacuoles, and lamellar bodies, which were typically present within distal cytoplasmic processes. In pyramidal CA1 neurons, Tat induction reduced the number of apical dendritic spines, while disrupting the distribution of synaptic proteins (synaptotagmin 2 and gephyrin) associated with inhibitory transmission but with minimal dendritic pathology and no evidence of pyramidal neuron death. Electrophysiological assessment of excitatory postsynaptic field potential at Schaffer collateral/commissural fiber-CA1 synapses showed near total suppression of LTP in mice expressing Tat. The loss in LTP coincided with disruptions in learning and memory.
  
  
  CONCLUSIONS
  Tat expression in the brain results in profound functional changes in synaptic physiology and in behavior that are accompanied by only modest structural changes and minimal pathology. Tat likely contributes to HAND by causing molecular changes that disrupt synaptic organization, with inhibitory presynaptic terminals containing synaptotagmin 2 appearing especially vulnerable.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia 23298, USA. sfitting@vcu.edu
authors.forename: Sylvia
authors.initials: S
authors.lastname: Fitting
authors.forename: Bogna M
authors.initials: BM
authors.lastname: Ignatowska-Jankowska
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bull
authors.forename: Robert P
authors.initials: RP
authors.lastname: Skoff
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: Laura E
authors.initials: LE
authors.lastname: Wise
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fox
authors.forename: Jianmin
authors.initials: J
authors.lastname: Su
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Medina
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Krahe
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.forename: William
authors.initials: W
authors.lastname: Guido
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D003214:Conditioning, Classical / Q000502:physiology; D003712:Dendrites / Q000378:metabolism; D005239:Fear / Q000502:physiology; D015696:Gene Products, tat / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D007858:Learning / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D013569:Synapses / Q000235:genetics* / Q000378:metabolism
chemical_list: D015696:Gene Products, tat