Unraveling the mechanisms of neurotoxicity in HIV type 1-associated dementia: Inhibition of neuronal synaptic transmission by macrophage secretory products

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Abstract

The cognitive and motor impairments of HIV-1-associated dementia (HAD) often result from neuronal damage of drop-out. In the infected human host, virus-infected immune-competent mononuclear phagocytes (MPs) (brain macrophages and microglia) are the target cells for HIV-1 and the producers of bioactive molecules that mediate neural damage. Indeed, in laboratory experiments, activated HIV-1-infected macrophages placed into human or rodent brain tissues induce neuronal apoptosis. Nonetheless, the mechanisms for neuronal dysfunction in HAD have yet to be discerned. To these ends, we studied the effects of HIV-1-infected monocyte-derived macrophage (MDM) secretions, electrophysiologically, on neuronal synaptic transmission. Bath application of HIV-1-infected MDM culture fluids onto rat hippocampal brain slices resulted in inhibition of evoked field excitatory postsynaptic potentials (EPSPs). In contrast, fluids from uninfected MDMs showed mild effects on the EPSPs. HIV-1-associated inhibition of EPSPs was enhanced by LPS activation, both for HIV-1-infected and uninfected MDMs. Importantly, paired-pulse facilitation ratio tests showed that factors secreted by HIV-1- infected MDMs acted transiently on presynaptic terminals, providing insights into the site of action and mechanism of the MDM-induced neuronal dysfunction. These results, taken together, demonstrate that factors produced as a consequence of MDM infection and activation affect neuronal synaptic transmission.

Original languageEnglish (US)
Pages (from-to)57-63
Number of pages7
JournalAIDS Research and Human Retroviruses
Volume15
Issue number1
DOIs
StatePublished - Jan 1 1999

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Synaptic Transmission
Dementia
HIV-1
Macrophages
Excitatory Postsynaptic Potentials
Brain
Inhibition (Psychology)
Macrophage Activation
Presynaptic Terminals
Microglia
Phagocytes
Baths
Rodentia
Apoptosis
Viruses
Infection

ASJC Scopus subject areas

  • Immunology
  • Virology
  • Infectious Diseases

Cite this

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title = "Unraveling the mechanisms of neurotoxicity in HIV type 1-associated dementia: Inhibition of neuronal synaptic transmission by macrophage secretory products",
abstract = "The cognitive and motor impairments of HIV-1-associated dementia (HAD) often result from neuronal damage of drop-out. In the infected human host, virus-infected immune-competent mononuclear phagocytes (MPs) (brain macrophages and microglia) are the target cells for HIV-1 and the producers of bioactive molecules that mediate neural damage. Indeed, in laboratory experiments, activated HIV-1-infected macrophages placed into human or rodent brain tissues induce neuronal apoptosis. Nonetheless, the mechanisms for neuronal dysfunction in HAD have yet to be discerned. To these ends, we studied the effects of HIV-1-infected monocyte-derived macrophage (MDM) secretions, electrophysiologically, on neuronal synaptic transmission. Bath application of HIV-1-infected MDM culture fluids onto rat hippocampal brain slices resulted in inhibition of evoked field excitatory postsynaptic potentials (EPSPs). In contrast, fluids from uninfected MDMs showed mild effects on the EPSPs. HIV-1-associated inhibition of EPSPs was enhanced by LPS activation, both for HIV-1-infected and uninfected MDMs. Importantly, paired-pulse facilitation ratio tests showed that factors secreted by HIV-1- infected MDMs acted transiently on presynaptic terminals, providing insights into the site of action and mechanism of the MDM-induced neuronal dysfunction. These results, taken together, demonstrate that factors produced as a consequence of MDM infection and activation affect neuronal synaptic transmission.",
author = "Huangui Xiong and Zheng, {Jialin C} and Michael Thylin and Gendelman, {Howard Eliot}",
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