Elsevier

Biological Psychiatry

Volume 73, Issue 5, 1 March 2013, Pages 443-453
Biological Psychiatry

Archival Report
Synaptic Dysfunction in the Hippocampus Accompanies Learning and Memory Deficits in Human Immunodeficiency Virus Type-1 Tat Transgenic Mice

https://doi.org/10.1016/j.biopsych.2012.09.026Get rights and content

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.

Section snippets

Animals and Doxycycline Administration

Glial fibrillary acidic protein-driven, doxycycline (DOX)-inducible, Tat transgenic male mice were used to evaluate the effects of the Tat protein on hippocampal structure, function, and behavior. The generation of DOX-inducible, brain-specific HIV-Tat transgenic mice has been previously reported (44) (Supplementary Methods in Supplement 1). Tat expression was induced with a specially formulated chow containing 6 mg/g DOX (Harlan, Indianapolis, Indiana), fed to control Tat− mice that lacked the

Tat-Induced Astroglial Pathology

To determine the extent to which Tat induction resulted in ultrastructural changes in astrocytes, electron microscopy of the hippocampal CA1 region was performed (Figure 1). Criteria for identifying astrocytes and neurons are provided in the figure legends. While astroglia in Tat−/DOX mice appeared normal (Figure 1A), pathologic changes were noted in many of the astrocytes in the CA1 region of Tat+/DOX mice (Figure 1B–F). Unlike in Tat−/DOX-treated mice, the cytoplasm of astrocytes from

Discussion

Human immunodeficiency virus associated neurocognitive disorders persist even in cART-treated individuals who are aviremic 13, 14, 15, 60. This suggests that once an individual becomes infected, restricting viral replication alone is insufficient to prevent neurocognitive damage. With improved survival in patients receiving cART, the manifestations of chronic exposure to low levels of viral and cellular toxins associated with HIV-1 infection become increasingly evident—especially in sanctuaries

References (95)

  • S. Fitting et al.

    Interactive comorbidity between opioid drug abuse and HIV-1 Tat: Chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons

    Am J Pathol

    (2010)
  • M.A. Fox et al.

    Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals

    Cell

    (2007)
  • P.H. Reddy et al.

    Amyloid beta, mitochondrial dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer's disease

    Trends Mol Med

    (2008)
  • A. Nath et al.

    Neurobiological aspects of human immunodeficiency virus infection: Neurotoxic mechanisms

    Prog Neurobiol

    (1998)
  • B. Bingol et al.

    Deconstruction for reconstruction: The role of proteolysis in neural plasticity and disease

    Neuron

    (2011)
  • A. Rodenas-Ruano et al.

    Distinct roles for ephrinB3 in the formation and function of hippocampal synapses

    Dev Biol

    (2006)
  • G.C. Brailoiu et al.

    Excitatory effects of human immunodeficiency virus 1 Tat on cultured rat cerebral cortical neurons

    Neuroscience

    (2008)
  • T.R. Soderling et al.

    Postsynaptic protein phosphorylation and LTP

    Trends Neurosci

    (2000)
  • T. Behnisch et al.

    HIV secreted protein Tat prevents long-term potentiation in the hippocampal CA1 region

    Brain Res

    (2004)
  • P.J. Strijbos et al.

    Neurotoxic mechanisms of transactivating protein Tat of Maedi-Visna virus

    Neurosci Lett

    (1995)
  • J.M. Fritschy et al.

    Gephyrin: Where do we stand, where do we go?

    Trends Neurosci

    (2008)
  • B. Luscher et al.

    Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses

    Pharmacol Ther

    (2004)
  • M.J. Kim et al.

    Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95

    Neuron

    (2007)
  • R.K. Fujimura et al.

    Polymerase chain reaction method for determining ratios of human immunodeficiency virus proviral DNA to cellular genomic DNA in brain tissues of HIV-infected patients

    J Virol Methods

    (1995)
  • D.O. Hebb

    The Organization of Behavior

    (1949)
  • J.E. Dayhoff

    Computational properties of networks of synchronous groups of spiking neurons

    Neural Comput

    (2007)
  • A. Globus et al.

    Loss of dendrite spines as an index of pre-synaptic terminal patterns

    Nature

    (1966)
  • M. Sheng et al.

    Postsynaptic signaling and plasticity mechanisms

    Science

    (2002)
  • E. Masliah et al.

    Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC Group. The HIV Neurobehavioral Research Center

    Ann Neurol

    (1997)
  • I.P. Everall et al.

    Cortical synaptic density is reduced in mild to moderate human immunodeficiency virus neurocognitive disorder. HNRC Group. HIV Neurobehavioral Research Center

    Brain Pathol

    (1999)
  • M. Day et al.

    Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models

    Nat Neurosci

    (2006)
  • R. Ellis et al.

    HIV and antiretroviral therapy in the brain: Neuronal injury and repair

    Nat Rev Neurosci

    (2007)
  • R.K. Heaton et al.

    HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study

    Neurology

    (2010)
  • R.K. Heaton et al.

    HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: Differences in rates, nature, and predictors

    J Neurovirol

    (2010)
  • J.C. McArthur et al.

    Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap

    Ann Neurol

    (2010)
  • P. Coleman et al.

    A focus on the synapse for neuroprotection in Alzheimer disease and other dementias

    Neurology

    (2004)
  • D.E. Brenneman et al.

    Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide

    Nature

    (1988)
  • S.A. Lipton

    Human immunodeficiency virus-infected macrophages, gp120, and N-methyl-D-aspartate receptor-mediated neurotoxicity

    Ann Neurol

    (1993)
  • N.J. Haughey et al.

    Involvement of inositol 1,4,5-trisphosphate-regulated stores of intracellular calcium in calcium dysregulation and neuron cell death caused by HIV-1 protein Tat

    J Neurochem

    (1999)
  • A. Nath

    Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia

    J Infect Dis

    (2002)
  • G.J. Jones et al.

    HIV-1 Vpr causes neuronal apoptosis and in vivo neurodegeneration

    J Neurosci

    (2007)
  • E.B. Dreyer et al.

    HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists

    Science

    (1990)
  • S.A. Lipton

    HIV-related neurotoxicity

    Brain Pathol

    (1991)
  • M. Kaul et al.

    Pathways to neuronal injury and apoptosis in HIV-associated dementia

    Nature

    (2001)
  • J. Sodroski et al.

    Location of the trans-activating region on the genome of human T-cell lymphotropic virus type III

    Science

    (1985)
  • B. Ensoli et al.

    Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation

    J Virol

    (1993)
  • H.C. Chang et al.

    HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region

    AIDS

    (1997)

    • Cited by (0)

    View full text
    Published by Elsevier Inc.