Scaling Synapses in the Presence of HIV

Abstract

A defining feature of HIV-associated neurocognitive disorder (HAND) is the loss of excitatory synaptic connections. Synaptic changes that occur during exposure to HIV appear to result, in part, from a homeostatic scaling response. Here we discuss the mechanisms of these changes from the perspective that they might be part of a coping mechanism that reduces synapses to prevent excitotoxicity. In transgenic animals expressing the HIV proteins Tat or gp120, the loss of synaptic markers precedes changes in neuronal number. In vitro studies have shown that HIV-induced synapse loss and cell death are mediated by distinct mechanisms. Both in vitro and animal studies suggest that HIV-induced synaptic scaling engages new mechanisms that suppress network connectivity and that these processes might be amenable to therapeutic intervention. Indeed, pharmacological reversal of synapse loss induced by HIV Tat restores cognitive function. In summary, studies indicate that there are temporal, mechanistic and pharmacological features of HIV-induced synapse loss that are consistent with homeostatic plasticity. The increasingly well delineated signaling mechanisms that regulate synaptic scaling may reveal pharmacological targets suitable for normalizing synaptic function in chronic neuroinflammatory states such as HAND.

HIV-1 Tat Length: Comparative and Functional Considerations

“…To our knowledge, there are no transgenic animal models that express Tat 101 (Soontornniyomkij et al, 2016;Langford et al, 2018;Green et al, 2019). The iTat model, which expresses Tat in a doxycycline-dependent manner that models chronic exposure, is a widely utilized model of HAND, however, it also does not express the Tat 101 protein (Fan et al, 2016;Langford et al, 2018).…”

Neurogranin: A Potential Biomarker of Neurological and Mental Diseases

“…The antiretroviral therapy has decreased the rates of mortality and morbidity in HIV-positive (HIV + ) patients and has decreased the incidence of HIV-associated dementia, which is the most severe stage of neuro-HIV ( Sinharay and Hammoud, 2019 ). Synaptic disruption is crucial in the mechanisms of cognitive impairment in HIV-1-infected patients ( Everall et al, 1999 ; Green et al, 2019 ). Compared with neuronal apoptosis and HIV-encephalitis, the dendritic injury due to HIV-1 infection is more closely related to cognitive impairments among HIV-associated neurocognitive disorder (HAND) patients ( Everall et al, 1999 ).…”

HIV gp120‐induced neuroinflammation potentiates NMDA receptors to overcome basal suppression of inhibitory synapses by p38 MAPK

“…The gp120‐evoked increase in the number of inhibitory synapses appears to be mediated by a homeostatic plasticity mechanism to counteract excessive excitation (Pozo and Goda ; Green et al . ). We did not detect significant cell death during a 24 h exposure to gp120, although others have described a 23–55% loss of neurons during a 24–72 exposure to gp120 concentrations ranging from 200 pM to 100 nM (Medders et al .…”

“…; Green et al . ). We posit that the gp120‐induced increase in inhibitory synapses is part of a coping mechanism that occurs during 24 h treatment with agents that potentiate NMDARs.…”

“…Thus, synaptic changes may be a mechanism to cope with over activation of NMDARs (Green et al . ). This study supports the idea that activation of potentiated GluN2A‐containing NMDARs increases inhibitory synapse number as an adaptive mechanism to counteract excess excitation and promote neuronal survival.…”