HIV-associated dementia (HAD) has become one of the leading causes of dementia in the young. The clinical syndrome includes the progressive development of psychomotor slowing and memory impairment. HIV productively infects microglial cells in the central nervous system. Release of viral products and host mediators such as cytokines into the brain parenchyma is believed to play a pivotal role in the pathogenesis of HAD. The present application is aimed at the characterization of the effects of the HIV regulatory protein Tat in synaptic transmission and plasticity. The best-characterized action of Tat is the transactivation of the HIV-1 genome. However, it is also actively released by HIV-1-infected cells and it displays several biologic activities on multiple cell types. Tat has been shown to activate phosphatidylinositol 3-kinase (PI3kinase) in neuronal and other cell types. We have recently observed that PI3-kinase activity is necessary for long term potentiation (LTP) of synaptic responses in the hippocampus. LTP is a form of neural plasticity believed to be a cellular correlate of learning and memory. Therefore, we propose to investigate the molecular and cellular bases for Tat's ability to modulate cellular excitability and its effects on hippocampal synaptic plasticity. The main hypothesis of this proposal is that Tat could interfere with hippocampal synaptic plasticity through the induction of PI3-kinase. Such an observation would support a crucial role for this viral product in the cognitive dysfunction of HIV-infected individuals. The results of the proposed study will advance the understanding of the pathogenesis of HAD.
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