NMDARs Adapt to Neurotoxic HIV Protein Tat Downstream of a GluN2A-Ubiquitin Ligase Signaling Pathway.

Synaptodendritic damage correlates with cognitive decline in HIV-associated neurocognitive disorder (HAND). In a cell culture model, we show that the HIV protein transactivator of transcription (Tat) initially potentiates NMDARs that then adapt to the presence of the toxin. Adaptation of NMDAR function was mediated by a GluN2A/Akt/Mdm2 pathway not previously linked to neuroinflammatory disorders such as HAND. Activation of this pathway caused a loss of synaptic NMDAR clusters. Decreased NMDAR function may result from a homeostatic response gone awry and underlie impaired synaptic function in HAND.