Worldwide, more than 35 million people are currently infected with the human immunodeficiency virus (HIV). Approximately half of HIV-infected patients in the U.S. experience cognitive impairment despite effective control of viral load with combination anti-retroviral therapy (cART). The neurological complications that stem from an HIV infection are known as HIV-associated neurocognitive disorders (HAND). HAND ranges in severity from subtle difficulties with day-to-day tasks to severe functional impairment requiring assistance to survive. Although cART has improved patient survival by effectively managing viral load, it is ineffective at treating the majority of HAND. Consequently, the prevalence of HAND remains persistently high. The symptoms of HAND correlate with neuronal damage, such as synapse loss and dendritic beading. Such synaptodendritic damage results from HIV-infected cells within the central nervous system (CNS) shedding neurotoxic agents, such as the HIV-1 protein transactivator of transcription (Tat). Tat potentiates N-methyl D-aspartate (NMDA) receptor function allowing excessive Ca2+ influx leading to neurotoxicity. In this dissertation, two studies are outlined investigating the mechanisms of NMDA receptor (NMDAR) dysfunction following exposure to Tat. The graphical abstract summarizes these studies. First, the effect of Tat on NMDAR function was investigated. This study showed that Tat caused a time-dependent, biphasic change in NMDAR function. Initially, Tat potentiated NMDAR function via the low-density lipoprotein receptor-related protein (LRP) and activation of Src tyrosine kinase. Subsequently, NMDAR function adapted by gradually returning to basal levels following 24 h exposure to Tat and eventually falling below control responses by 48 h. Adaptation resulted from activation of a nitric oxide synthase (NOS), soluble guanylate cyclase (sGC), cGMP-dependent protein kinase (PKG) signaling pathway. Next, effectors downstream of PKG responsible for adaptation of NMDAR function were identified. Tat activated a signaling pathway including the small GTPase RhoA and Rho-associated protein kinase (ROCK). RhoA/ROCK activation caused remodeling of the actin cytoskeleton resulting in reduced NMDAR function. Taken together, these studies indicate that Tat causes a biphasic change in NMDAR function. Potentiation of NMDAR function is mediated by LRP-dependent activation of Src kinase; adaptation of NMDAR function occurs after activation of a NOS/sGC/PKG signaling pathway leading to RhoA/ROCK-mediated remodeling of the actin cytoskeleton. Adaptation of NMDAR function may be a neuroprotective mechanism to reduce excess Ca2+ influx and prevent neurotoxicity. These studies provide molecular and temporal detail of the dynamic changes in NMDAR function following exposure to Tat and offer insight into potential therapeutic targets for the treatment of HAND.