HIV Tat Protein in CB1 Receptor-Mediated Signaling in Central Olfactory Circuits
Marijuana (cannabis) is the most commonly abused illicit drug. THC, the bioactive ingredient of the drugs marijuana and hashish, activates cannabinoid receptors (CB1R) in the brain in the same manner as brain-produced endogenous cannabinoids (endocannabinoids, eCBs). Cannabinoids have important roles in healthy and pathological brains. In the brain, the hallmark feature of eCBs is to mediate forms of synaptic plasticity through retrograde signaling from activated postsynaptic neurons to presynaptic interneurons to reduce presynaptic release of GABA (Depolarization-Induced Supression of Inhibition, DSI) or glutamate. Marijuana use is prevalent among HIV-infected populations. Since marijuana is widely used and gains more social acceptability in the U.S., it is critical to understand if, and how, marijuana and cannabinoids impact HIV. Nearly 50% of HIV-infected individuals suffer with HIV-associated neurocognitive disorders (HAND). We consider it crucial to understand if, and how, marijuana and cannabinoids impact HAND. We propose to identify how the cellular and molecular mechanisms of cannabinoid signaling cross-react with HIV-infection in the brain. The HIV trans-activator of transcription (Tat) is one of the neurotoxins and thought to be a key player in the neuropathogenesis of HAND. We will determine if the retrograde signaling function of the eCB system is altered in the presence of HIV. Specifically, we will examine the effects of Tat on the eCB system in acute brain slices of the mouse main olfactory bulb (MOB). Using whole-cell patch-clamp electrophysiology, we will measure changes in retrograde eCB signaling following exposure to Tat. We aim to test the hypothesis that Tat will regulate (a) intrinsic properties olfactory interneurons and (b) the effects of eCBs on these interneurons in the MOB using acute brain slices and patch-clamp electrophysiology. In Aim 2 will test the hypothesis that Tat modifies eCB-mediated functional (synaptic) connectivity of MOB output neurons. This aim will determine effects of Tat on cannabinoid- mediated retrograde signaling (DSI) in the MOB. Potential outcomes include a change of intrinsic and synaptic properties of olfactory interneurons as well as changes of the magnitude of retrograde signaling, measured as DSI in MOB output neurons in response to Tat. Any change in CB1R function in vitro would suggest that eCB-mediated neuroprotection may be reduced in vivo and that Tat contributes to synaptodendritic injury in HAND.