HIV and opiates dysregulate K+- Cl- cotransporter 2 (KCC2) to cause GABAergic dysfunction in primary human neurons and Tat-transgenic mice

NEUROBIOLOGY OF DISEASE

卷:141

Article

Barbour, Aaron J.^1,2  Hauser, Kurt F.^1,2,3,4  McQuiston, A. Rory^1,2  Knapp, Pamela E.^1,2,3,4 

[1] Virginia Commonwealth Univ, Dept Anat, Sch Med, Richmond, VA 23298 USA

[2] Virginia Commonwealth Univ, Dept Neurobiol, Sch Med, Richmond, VA 23298 USA

[3] Virginia Commonwealth Univ, Sch Med, Pharmacol & Toxicol, Richmond, VA 23298 USA

[4] Virginia Commonwealth Univ, Inst Drug & Alcohol Studies, Sch Med, Richmond, VA 23298 USA

关键词: neuroHIV;    Opioid abuse;    C-C motif chemokine receptor 5 (CCR5);    Intracellular chloride homeostasis;    KCC2;    GABA(A) hyperpolarization;    Archon1;    GCaMP6f;   

DOI  :  10.1016/j.nbd.2020.104878

来源: Elsevier

【 摘 要 】

Approximately half of people infected with HIV (PWH) exhibit HIV-associated neuropathology (neuroHIV), even when receiving combined antiretroviral therapy. Opiate use is widespread in PWH and exacerbates neuroHIV. While neurons themselves are not infected, they incur sublethal damage and GABAergic disruption is selectively vulnerable to viral and inflammatory factors released by infected/affected glia. Here, we demonstrate dimin ished K+- Cl- cotransporter 2 (KCC2) levels in primary human neurons after exposure to HIV-1 or HIV-1 proteins +/- morphine. Resulting disruption of GABA(A)R-mediated hyperpolarization/inhibition was shown using genetically-encoded voltage (Archon1) and calcium (GCaMP6f) indicators. The HIV proteins Tat (acting through NMDA receptors) and R5-gpl 20 (acting via CCR5) but not X4-tropic gp120 (acting via CXCR4), and morphine (acting through mu-opioid receptors) all induced KCC2 loss. We demonstrate that modifying KCC2 levels or function, or antagonizing NMDAR, CCR5 or MOR rescues KCC2 and GABA(A)R-mediated hyperpolarization/inhibition in HIV, Tat, or gp120 +/- morphine-exposed neurons. Using an inducible, Tat-transgenic mouse neuroHlV model, we found that chronic exposure to Tat also reduces KCC2. Our results identify KCC2 as a novel therapeutic target for ameliorating the pathobiology of neuroHIV, including PWH exposed to opiates.