HIV gp120-induced synaptic changes -- modulation by the endocannabinoid system and NMDARs

Abstract

37.9 million people worldwide are living with HIV. Nearly half of these individuals develop HIV-associated neurocognitive disorder (HAND). Symptoms range from subclinical cognitive deficits to severe dementia that impairs daily function and may cause death. Combination antiretroviral therapy (cART) has significantly decreased the incidence of severe HIV dementia and encephalitis; however, HAND prevalence remains high and may be increasing due to the prolonged life span of HIV patients. Currently, there is no effective treatment for improving cognitive function in HAND patients. Thus, understanding the mechanism and possible avenues for modulating HIV-induced cognitive decline is important. HIV neurotoxicity is mainly mediated by factors released by infected cells. The HIV envelope protein, gp120, is shed by infected cells and is a potent neurotoxin causing excitotoxicity and loss of excitatory synapses. Synaptic damage is reversible and correlates with cognitive decline in HAND patients. In this dissertation, I explored mechanisms of HIV gp120-induced changes in the number of excitatory and inhibitory synapses. Balance between excitatory and inhibitory synapses is important for controlling network excitability and maintaining normal neural function. The endocannabinoid (eCB) system and NMDA receptors (NMDARs) were investigated for their role in gp120-induced synaptotoxicity. HIV gp120 induces loss of excitatory synapses via a neuroinflammatory pathway; the endocannabinoid (eCB) system is a potential target to modulate neuroinflammation. In the first study, I demonstrated that inhibition of monoacylglycerol lipase (MGL), the enzyme that degrades the eCB 2-arachidonoylglycerol (2-AG), using the specific inhibitor JZL184, blocked gp120-induced excitatory synapse loss. Inhibition of MGL suppressed gp120-induced release of the inflammatory cytokine interleukin-1β (IL-1β) through enhanced activation of cannabinoid type 2 receptors (CB2Rs), and decreased production of prostaglandin E2 (PGE2) further decreases neuroinflammation. In the second study, I showed that gp120 increases the number of inhibitory synapses through the same IL-1β-mediated neuroinflammatory pathway. Activation of the tyrosine kinase Src potentiated GluN2A NMDARs to overcome a tonic suppression of inhibitory synapses by p38 mitogen-activated protein kinase. In the third study, a mechanism for excitatory synaptogenesis was examined. I showed that presynaptic GluN2B NMDARs control spontaneous glutamate release, and inhibition of these receptors induces synaptogenesis when evoked neurotransmission is impaired. Taken together, these studies elucidate mechanisms of gp120-induced synaptotoxicity. Decreased excitatory and increased inhibitory synaptic input may be adaptive mechanisms through which neurons counteract excessive excitation-induced by HIV neurotoxins. Because these synaptic changes correlate with cognitive decline, they may indicate that a neuroprotective mechanism has gone awry. By determining the pathways activated by HIV gp120, this dissertation provides new insight into synaptotoxicity-associated with HAND and identifies novel targets for therapeutic agents that provide neuroprotection.