The alpha7-nicotinic receptor contributes to gp120-induced neurotoxicity: implications in HIV-associated neurocognitive disorders

Currently, there are no specific therapies to treat HIV-1 associated neurocognitive disorders (HAND). The HIV-1 envelope, gp120, induces neuropathological changes similar to those in HAND patients; furthermore, it triggers an upregulation of the alpha 7-nicotinic acetylcholine receptor (alpha 7-naChR), facilitating intracellular calcium overload and neuronal cell death. Using a gp120(IIIB)-transgenic mouse (gp120-tgm) model, we demonstrate that alpha 7-naChRs are upregulated on striatal neurons. activation of alpha 7-naChRs leads to an increase in both intracellular calcium and percentage of apoptotic cells, which can be abrogated by antagonizing the receptor, suggesting a role for alpha 7-naChRs in gp120-induced neurotoxicity. Moreover, we demonstrate for the first time that gp120-tgm have learning deficiencies on a striatum-dependent behavioral task. They also show locomotor deficiencies, which improved with alpha 7-naChR antagonists, further supporting a role for this receptor in gp120-induced neurotoxicity. Together, these results uncover a new mechanism through which gp120-induced modulation of alpha 7-naChRs in the striatum can contribute to HaND development.