Despite the success of antiretroviral therapy in suppressing viral load, nearly half of the 37 million people infected with HIV experience cognitive and motor impairments, collectively classified as HIV-associated neuro-cognitive disorders (HAND). In the CNS, HIV-infected microglia release neurotoxic agents that act indirectly to elicit excitotoxic synaptic injury. HIV trans-activator of transcription (Tat) protein is one such neurotoxin that is thought to play a major role in the neuropathogenesis of HAND. The endocannabinoid (eCB) system provides on-demand neuroprotection against excitotoxicity, and exogenous cannabinoids attenuate neurotoxicity in animal models of HAND. Whether this neuroprotective system is altered in the presence of HIV is unknown. Here, we examined the effects of Tat on the eCB system in rat primary hippocampal cultures. Using whole-cell patch-clamp electrophysiology, we measured changes in retrograde eCB signaling following exposure to Tat. Treatment with Tat significantly reduced the magnitude of depolarization-induced suppression of excitation (DSE) in a graded manner over the course of 48 h. Interestingly, Tat did not alter this form of short-term synaptic plasticity at inhibitory terminals. The Tat-induced decrease in eCB signaling resulted from impaired CB1 receptor (CB1R)-mediated presynaptic inhibition of glutamate release. This novel loss-of-function was particu-larly dramatic for low-efficacy agonists such as the eCB 2-arachidonoylglycerol (2-AG) and D9-tetrahydrocan-nabinol (D9-THC), the main psychoactive ingredient in marijuana. Our observation that HIV Tat decreases CB1R function in vitro suggests that eCB-mediated neuroprotection may be reduced in vivo; this effect of Tat may contribute to synaptodendritic injury in HAND.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health (NIH) Grants DA007304 and DA044809 (to S.A.T.). M.M.W. was supported by the NIH Training Grant T32 DA007097. Acknowledgements: We thank Dr. Tamas Balla (National Institute of Child Health and Human Development, National Institutes of Health) for the DAG biosensor.
This work was supported by National Institutes of Health (NIH) Grants DA007304 and DA044809 (to S.A.T.). M.M.W. was supported by the NIH Training Grant T32 DA007097.
© 2020 Wu and Thayer.
- CB receptor
- HIV Tat