ArticlePLoS biology2018
HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model.
Article in PLoS biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
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- The autism-associated loss of δ-catenin functions disrupts social behavior.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- 3D engineered tissue models for studying human-specific infectious viral diseases.Bioactive materials · 2023Review
- HIV and FIV glycoproteins increase cellular tau pathology via cGMP-dependent kinase II activation.Journal of cell science · 2022Article
- Phosphorylation of the AMPA receptor subunit GluA1 regulates clathrin-mediated receptor internalization.Journal of cell science · 2021Article
- Improved neurocognitive performance in FIV infected cats following treatment with the p75 neurotrophin receptor ligand LM11A-31.Journal of neurovirology · 2021Article
- Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced CaNeurobiology of aging · 2019Article
- Aging sensitizes male mice to cognitive dysfunction induced by central HIV-1 gp120.Experimental gerontology · 2019Article
- HIV Associated Neurodegenerative Disorders: A New Perspective on the Role of Lipid Rafts in Gp120-Mediated Neurotoxicity.Current HIV research · 2018Review
- Selective coactivation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid-induced synaptic dysfunction.The Journal of biological chemistryArticle
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
Over half of individuals infected with human immunodeficiency virus (HIV) suffer from HIV-associated neurocognitive disorders (HANDs), yet the molecular mechanisms leading to neuronal dysfunction are poorly understood. Feline immunodeficiency virus (FIV) naturally infects cats and shares its structure, cell tropism, and pathology with HIV, including wide-ranging neurological deficits. We employ FIV as a model to elucidate the molecular pathways underlying HIV-induced neuronal dysfunction, in particular, synaptic alteration. Among HIV-induced neuron-damaging products, HIV envelope glycoprotein gp120 triggers elevation of intracellular Ca2+ activity in neurons, stimulating various pathways to damage synaptic functions. We quantify neuronal Ca2+ activity using intracellular Ca2+ imaging in cultured hippocampal neurons and confirm that FIV envelope glycoprotein gp95 also elevates neuronal Ca2+ activity. In addition, we reveal that gp95 interacts with the chemokine receptor, CXCR4, and facilitates the release of intracellular Ca2+ by the activation of the endoplasmic reticulum (ER)-associated Ca2+ channels, inositol triphosphate receptors (IP3Rs), and synaptic NMDA receptors (NMDARs), similar to HIV gp120. This suggests that HIV gp120 and FIV gp95 share a core pathological process in neurons. Significantly, gp95's stimulation of NMDARs activates cGMP-dependent protein kinase II (cGKII) through the activation of the neuronal nitric oxide synthase (nNOS)-cGMP pathway, which increases Ca2+ release from the ER and promotes surface expression of AMPA receptors, leading to an increase in synaptic activity. Moreover, we culture feline hippocampal neurons and confirm that gp95-induced neuronal Ca2+ overactivation is mediated by CXCR4 and cGKII. Finally, cGKII activation is also required for HIV gp120-induced Ca2+ hyperactivation. These results thus provide a novel neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND.
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