The Phospholipid Mediator Platelet-Activating Factor Mediates Striatal Synaptic Facilitation

Abstract

The phospholipid mediator platelet-activating factor (PAF), an endogenous modulator of glutamatergic neurotransmission, can also be secreted by brain mononuclear phagocytes during HIV-1 infection. Platelet-activating factor can induce neuronal apoptosis by NMDA receptor-dependent and independent mechanisms. We now demonstrate that acute administration of sublethal doses of PAF to striatal slices augments synaptic facilitation in striatal neurons following high-frequency stimulation, which can be blocked by PAF receptor antagonists, suggesting that striatal synaptic facilitation can be augmented by PAF receptor agonism. We also demonstrate that repeated sublethal doses of PAF during tetanic stimulation can greatly increase the magnitude of postsynaptic potentials and action potentials, but a lethal dose of PAF destroys the capacity of corticostriatal synapses to achieve this augmented synaptic facilitation. Thus, the relative concentration and temporal pattern of PAF expression at glutamatergic synapses may govern whether it acts in a physiologic or pathophysiologic manner during striatal neurotransmission.

Human Immunodeficiency Virus-1 Tat Activates Calpain Proteases via the Ryanodine Receptor to Enhance Surface Dopamine Transporter Levels and Increase Transporter-Specific Uptake andVmax

“…The sum of this data, together with previous work demonstrating that the HIV mediators Tat and PAF increase neuronal metabolic and synaptic activity (Haughey et al, 2001; Bellizzi et al, 2005; Perry et al, 2005b; Lu et al, 2007), suggests DAergic tone may be increased in HAND. Bolstering this concept, PAF also increases membrane DAT by mechanisms similar to those shown here for Tat (unpublished data).…”

“…While cART can ameliorate or even reverse the course of HAND in some HIV-infected persons (Gendelman et al, 1998), the severity of neurocognitive impairment at cART initiation is the strongest predictor of persistent neurological deficits despite ongoing cART (Tozzi et al, 2007). Work from our and others’ laboratories has shown that the phospholipid mediator platelet-activating factor (PAF) and Tat can induce reversible synaptic dysfunction prior to cell death (Perry et al, 2005b; Lu et al, 2007; Kim et al, 2008), and elevated levels of PAF may render “normal” physiologic synaptic activity excitotoxic (Bellizzi et al, 2005). …”

HIV-1 Glycoprotein 120 Enhancement of N-Methyl-D-Aspartate NMDA Receptor-Mediated Excitatory Postsynaptic Currents: Implications for HIV-1-Associated Neural Injury

“…Gp120 also acts on postsynaptic NMDARs, contributing further to the enhancement of EPSC NMDAR . Another possibility is that gp120 activates glial cells and the activated glial cells release cytokines, chemokines and amino acids, such as CCL-2, platelet-activating factor and glutamate, leading to an enhancement of EPSCNMDAR in the hippocampal slices (Epstein and Gelbard, 1999; Lu et al, 2007; Zhou et al, 2016). Further experimentation is needed to confirm this possibility.…”

Common Transcriptional Signatures in Brain Tissue from Patients with HIV-Associated Neurocognitive Disorders, Alzheimer’s Disease, and Multiple Sclerosis

“…In AD, synaptic failure was correlated with accumulation and post-synaptic binding of beta-amyloid oligomers (Wilcox et al 2011; Yu and Lu 2012) and accumulation of phosphorylated tau in dendritic spines (Hoover et al 2010). The mechanisms of synaptic injury in HAND are not fully understood but role of factors secreted by HIV-infected macrophages including HIV Tat protein and platelet-activating factor has been suggested (Lu et al 2007; Lu et al 2011). Regardless of the proximal stimuli for synaptic injury, these results support the notion that some core cellular processes mediating this impairment in HAND and AD are similar.…”