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

The cognitive and motor impairments of HIV-1-associated dementia (HAD) ofte n result from neuronal damage of drop-out. In the infected human host, viru s-infected immune-competent mononuclear phagocytes (MPs) (brain macrophages and microglia) are the target cells for HIV-1 and the producers of bioacti ve molecules that mediate neural damage. Indeed, in laboratory experiments, activated HIV-l-infected macrophages placed into human or rodent brain tis sues induce neuronal apoptosis, Nonetheless, the mechanisms for neuronal dy sfunction in HAD have yet to be discerned. To these ends, we studied the ef fects of HIV-l-infected monocyte-derived macrophage (MDM) secretions, elect rophysiologically, on neuronal synaptic transmission. Bath application of H IV-l-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-l-associated inhibition of EPSPs was enhanced by LPS activation, both f or HIV-l-infected and uninfected MDMs, Importantly, paired-pulse facilitati on ratio tests showed that factors secreted by HIV-l-infected MDMs acted tr ansiently on presynaptic terminals, providing insights into the site of act ion and mechanism of the MDM-induced neuronal dysfunction, These results, t aken together, demonstrate that factors produced as a consequence of MDM in fection and activation affect neuronal synaptic transmission.