HIV Tat protein selectively impairs CB1 receptor-mediated presynaptic inhibition at excitatory but not...

HIV Tat protein selectively impairs CB1 receptor-mediated presynaptic inhibition at excitatory but not..., 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 neurocognitive disorders (HAND). In the central nervous system, HIV-infected microglia release neurotoxic agents that act indirectly to elicit excitotoxic synaptic injury.,

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 neurocognitive disorders (HAND). In the central nervous system, HIV-infected microglia release neurotoxic agents that act indirectly to elicit excitotoxic synaptic injury. HIV Tat (trans-activator of transcription) 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-mediated presynaptic inhibition of glutamate release. This novel loss-of-function was particularly dramatic for low efficacy agonists such as the eCB 2-arachidonoylglycerol and ⁹-tetrahydrocannabinol, the main psychoactive ingredient in marijuana. Our observation that HIV Tat decreases CB₁ receptor function in vitro suggests that eCB-mediated neuroprotection may be reduced in vivo; this effect of Tat may contribute to synaptodendritic injury in HAND.

Significance statement Activation of the eCB system protects against excitotoxicity. Whether this neuroprotection is altered in the presence of HIV is unknown. We show for the first time in an in vitro model of HIV neurotoxicity that an HIV protein selectively impairs eCB-mediated synaptic plasticity at excitatory but not inhibitory terminals. This selective effect of an HIV protein may unbalance synaptic networks, exacerbating the damage that underlies HAND. Thus, protecting or enhancing eCB signaling may attenuate the symptoms of HAND.

, admin,