RESUMEN
HIV-associated neurocognitive disorders afflict approximately half of HIV-infected patients. HIV-infected cells within the CNS release neurotoxic viral proteins such as the transactivator of transcription (Tat). Tat caused a biphasic change in NMDAR function; NMDA-evoked increases in intracellular Ca(2+) were initially potentiated following 16 h exposure to Tat and then adapted by gradually returning to baseline by 24 h. Following Tat-induced NMDAR potentiation, a RhoA/Rho-associated protein kinase (ROCK) signaling pathway was activated; a subsequent remodeling of the actin cytoskeleton reduced NMDA-evoked increases in intracellular Ca(2+) . Pharmacologic or genetic inhibition of RhoA or ROCK failed to affect potentiation, but prevented adaptation of NMDAR function. Activation of RhoA/ROCK signaling increases the formation of filamentous actin. Drugs that prevent changes to filamentous actin blocked adaptation of NMDAR function following Tat-induced potentiation, whereas stimulating either depolymerization or polymerization of actin attenuated NMDAR function. These findings indicate that Tat activates a RhoA/ROCK signaling pathway resulting in actin remodeling and subsequent reduction of NMDAR function. Adaptation of NMDAR function may be a mechanism to protect neurons from excessive Ca(2+) influx and could reveal targets for the treatment of HIV-associated neurocognitive disorders.
