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Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice.
- Source :
-
Biological psychiatry [Biol Psychiatry] 2013 Mar 01; Vol. 73 (5), pp. 443-53. Date of Electronic Publication: 2012 Dec 04. - Publication Year :
- 2013
-
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.<br />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.<br />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.<br />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.<br /> (Published by Elsevier Inc.)
- Subjects :
- Animals
Astrocytes metabolism
Behavior, Animal physiology
Cell Death physiology
Conditioning, Classical physiology
Dendrites metabolism
Fear physiology
Gene Products, tat metabolism
HIV-1 metabolism
Hippocampus physiopathology
Maze Learning physiology
Memory Disorders metabolism
Memory Disorders physiopathology
Mice
Mice, Transgenic
Neurons metabolism
Synapses metabolism
Gene Products, tat genetics
HIV-1 genetics
Hippocampus metabolism
Learning physiology
Memory physiology
Memory Disorders genetics
Synapses genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2402
- Volume :
- 73
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Biological psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 23218253
- Full Text :
- https://doi.org/10.1016/j.biopsych.2012.09.026