Selective pharmacological inhibition of tonic currents indic
Selective pharmacological inhibition of tonic currents indicated that the effects of gp120 are predominantly mediated by α5-containing GABAARs. The other dominant subtype that contributes to tonic current in the hippocampus, the δ-containing GABAAR, was unaffected by gp120 treatment. Additionally, immunocytochemistry experiments showed an increase in surface expression of α5-containing GABAARs. While other subtypes of GABAARs may also be upregulated, the α5-containing GABAAR appears to be the predominant subtype upregulated by gp120. Mice deficient in the α5 subunit actually perform better in hippocampal-dependent cognitive tests than their wildtype counterparts (Collinson et al., 2002). Indeed, reducing tonic inhibition ameliorates cognitive impairment in animal models of Down syndrome (Vidal et al., 2018), Alzheimer's disease (Wu et al., 2014) and stroke (Clarkson et al., 2010). Additionally, pharmacological inhibition of α5-containing GABAARs is well tolerated in rodents and humans (Rudolph and Mohler, 2014), in Cerdulatinib to inhibition of synaptic GABAA receptors which produces anxiety and seizures (Baram and Snead, 1990; Sanders and Shekhar, 1995). Thus, this study has important clinical implications because the drug used to inhibit the tonic inhibitory currents, basmisanil, is also being tested as a therapeutic to improve cognitive function in schizophrenia patients (NCT02953639; http://www.clinicaltrials.gov).
This report shows for the first time that gp120 upregulates α5-containing GABAARs, which may provide a selective pharmacological target within the GABAergic system of importance to HAND. Future studies will determine whether gp120-induced increases in tonically active GABAARs dampen neuronal excitability in vivo and impair cognitive function. If so, drugs that inhibit α5 GABAARs might improve cognitive function in HAND patients.
Conflicts of interest The authors declare no conflicts of interest. This work was supported by a grant from the National Institute on Drug Abuse, National Institutes of Health (DA07304) to S.A.T.
INTRODUCTION HIV infection is associated with increased risk for infectious and noninfectious chronic pulmonary complications including tuberculosis, emphysema, venous thromboembolism, pulmonary hypertension and lung cancer.1, 2 In a large cohort of VA patients, HIV-positive status conferred a nearly 2-fold increased risk of pulmonary fibrotic changes in older patients independent of multiple covariates. Additionally, in a cross-sectional multicenter cohort, fibrosis-like changes were present on computed tomography in approximately one-third of HIV-positive individuals. Despite these clinical and radiographic findings, the underlying mechanism(s) by which HIV predisposes to fibrotic changes in the lung has yet to be determined. In particular, it is unclear whether changes are a consequence of the increased frequency of pulmonary infections and postinfectious lung remodeling, or whether they are directly attributed to HIV-related proteins and their effects on cell signaling and function. Pulmonary fibrosis, or lung tissue scarring, is due to excessive deposition of collagen and extracellular matrix in the lung, which may lead to reduction in pulmonary function, impairment of gas exchange and resultant increase in respiratory symptoms such as dyspnea and cough. While fibrosis can be initiated by a variety of insults, the key effector cell is the myofibroblast, which is believed to originate from at least 3 sources: native lung fibroblasts undergoing fibroblast-to-myofibroblast transdifferentiation, pulmonary epithelial cells undergoing epithelial-to-mesenchymal transition and circulating fibrocytes. Regardless of their origin, myofibroblasts are characterized by production of α-smooth muscle actin (α-SMA) stress fibers, and are believed to be responsible for the majority of excess collagen and extracellular matrix production seen in pulmonary fibrosis.