Anomalies of GABAergic system associated with HIV-1 infection


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Human immunodeficiency virus-1 (HIV) infection of the central nervous system results in cognitive and behavioral dysfunctions diagnosed as HIV-associated dementia. Findings of lowered concentrations of γ-Aminobutyric acid (GABA) synthesizing enzymes in brains of HIV-infected patients suggest іmpаired GABAergic inhibitory neurotransmission аnalоgous to neurological and psychiatric disorders such as Parkinson’s disеаse and schizophrenia. In this study I performed investigations into the neurochemical characteristics and neuropathological, neurocognitive and virological associations of dysfunctions of GABAergic inhibitory neurotransmission in HIV-infected brains using the resources of the National NeuroAIDS Tissue Consortium, including clinical data and brain tissue from 515 аutоpsy cases. Lowered GABAergic transcripts were linked to the higher expression of immune and endothelial cell type markers and were associated with the decrease of astroglial enzyme glutamine synthetase. No evidences were found that GABAergic anomalies are driven by replicating virus or associated with the highly active antiretroviral treatment, drug abuse history, or neuropathology of HIV encephalitis. Concentrations of GABA synthesizing enzymes were substantially reduced in all three populations of viable interneurons and associated with higher interneuronal dopamine receptor 2 (DRD2) expression. Investigation into regional distribution of GABAergic anomaly showed decrease of GABAergic transcripts in all cortical and subcortical brain regions. Low inhibitory tone in the prefrontal cortex was strongly linked to poor verbal fluency tasking, while in the anterior cingulate cortex it was associated with worse performance in broad spectrum of functional tests. Reduced concentration of GABA synthesizing enzymes in the anterior cingulate cortex results in the upregulation of astroglial-expressed GABA transporter 1 in glia limitans and abnormal increase of regional blood flow. Further investigations into the association between impaired inhibitory transmission and higher expression of endothelial cell markers revealed that damage to basal lamina and loss of pericytes observed in HIVinfected brain specimens was associated with the loss of GABAergic innervations of cortical microvessels. This dissertation study demonstrated that HIV infection is associated with abnormal GABAergic inhibitory transmission that likely represents a process of synaptic plasticity. HIV-associated neurocognitive impairments were attributed to abnormal cognitive functionality that results from a complex failure to properly synchronize frontocortical output and to deactivate anterior cingulate region.