The HIV-1 viral protein Tat modulates glutamate and GABA exocytosis from human and mouse neocortical nerve endings by acting at different binding sites

Abstract

Background Central Nervous System (CNS) disorders often accompany the acquired immunodeficiency syndrome (AIDS) and are typified by neuropsychiatric symptoms, such as cognitive and motor impairments, sometimes paralleled by neuropathological hallmarks. Collectively, these events are referred to as HIV-1 associated dementia (HAD). Before the advent of the Highly Active Antiretroviral Therapy (HAART), about 20% of adult patients, but as many as 40% of children/adolescent infected subjects developed HAD. Nowadays, in the era of HAART, the prevalence of HAD has decreased, but a more subtle form of disorder, referred to as Minor Cognitive Motor Disorder (MCMD), has emerged in about 20% of symptomatic HIV-1 seropositive patients, including those receiving HAART. This work was aimed at investigating the impact of the HIV-1 viral protein Tat on central neurotransmission since this protein has been proposed as one of the viral component involved in the onset of central neuropsychiatric symptoms. Methods The approach used was the up-down superfusion of purified synaptosomes isolated from human neocortical specimens removed during neurosurgery from consenting patients suffering of brain tumours. Experiments were also carried out by using mouse purified synaptosomes or slices in an attempt to propose an animal model suitable to investigate Tat-induced modification to central nervous system. Functional studies were paralleled by biochemical investigation on the existence of receptor protein potential involved in the effects observed and changes to second messenger production. Results