Affiliation: College of Arts and Sciences, Department of Psychology and Neuroscience
This is a slide deck with a brief description of Benjamin Gorman's 2020 SURF project. The below is the text of an abstract submitted along the results of this project to a North Carolina research symposium.
While antiretroviral therapy (ART) has dramatically reduced human immunodeficiency virus type 1 (HIV-1) mortality, ART cannot eliminate viral reservoirs in the brain and thus HIV-1 associated neurocognitive disorder (HAND) persists in 30-50% of patients. HIV-1 proteins, such as transactivator of transcription (Tat), have been shown to contribute to synaptodendritic injuries and inflammation correlated with HAND. One potential therapeutic target is the endogenous cannabinoid system.
Activation of cannabinoid receptors (CBR), which include CB1R, CB2R, and GPR18, have been shown to induce anti-inflammatory effects in various neurodegenerative disease models. CB2R and GPR18 are expressed on microglia, which are significant HIV reservoirs and have been implicated in HAND neuropathogenesis. These receptors are activated by a relatively novel monoacylglycerol lipase (MAGL) inhibitor through upregulation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Despite potential clinical viability, the relationship between microglia, HAND, and CB2R and/or GPR18 signaling is not well understood.
To elucidate the microglia-mediated indirect effects of the Tat on neuronal function, the present study uses primary microglia and prefrontal cortex neuron culture models derived from postnatal day 1 and embryonic day 15–16 CD57/BL6 mice, respectively. Microglia cultures at DIV15 are treated with Tat, ABX1431, CB2R and GPR18 antagonists. Intracellular calcium levels, dendritic morphology, and neuronal injury are measured upon exposure to secretions of treated microglia, and microglial cytokine release is quantified. We hypothesize that Tat-exposed microglia will demonstrate increased production of various proinflammatory cytokines and induce dysregulation in neuronal health, with Abx1431 treatment attenuating these effects, possibly in a CB2R- or GPR18-dependent manner.