Differential selectivity of microglia and astrocytes in HIV-1 gp120-induced synaptic pruning

Synapse loss is a common neuropathology in the CNS of HIV patients, likely contributing to neurological complications such as neurocognitive disorders and pain. However, the underlying mechanism remains poorly understood. Here, we show microglia- and astrocyte-mediated synaptic pruning of excitatory and inhibitory synapses in the frontal cortex (FC) and spinal dorsal horn (SDH) of HIV-1 gp120 transgenic (gp120Tg) mice compared with the wild-type (WT). Confocal imaging and 3D reconstruction revealed a significant increase of internalized synaptic elements in microglia and astroglia in gp120Tg mice, in a region- and synapse-type-specific manner. Microglia in the FC of gp120Tg mice showed increased pruning activity on the pre-synaptic but not post-synaptic compartment of both excitatory and inhibitory synapses. In contrast, microglia in the SDH of gp120Tg mice had increased pruning activity of both pre- and post-synaptic compartments excitatory and inhibitory compartments in the SDH. However, astrocytes in the gp120 transgenic model increased their pruning activity of both the pre- and post-synaptic compartments of excitatory but not inhibitory synapses in the FC and the SDH. We confirmed synaptic engulfment in viral reservoirs in the brain tissues of human HIV patients. These findings provide important insights into the pathogenic mechanism of synapse loss induced by HIV.