Role of Glia in the Development of Ethanol Tolerance PDF Download

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Languages : en
Pages : 124

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Book Description
Despite widespread abuse, high socioeconomic costs, and substantial research investment, the basic mechanisms of alcohol action on the brain remain poorly understood. This is partly due to the physiological complexity of alcohol's effects and the long term progressive nature of alcohol use disorders (AUDs). Further, mammalian models of AUD endophenotypes require high levels of resources and time. One approach that has promise is to use invertebrate model organisms to understand the molecular and cellular mechanisms of behavioral adaptations to acute ethanol exposure. The fruit fly Drosophila, is a classic model organism for defining the molecules and neural circuits that drive animal behavior. The molecular makeup of the fly brain is remarkably conserved with that of mammals. Moreover, both flies and humans have a long history of association with alcohol, suggesting that behaviors like craving, drinking, and reward are coded similarly. Indeed, dopamine signaling underlies the hyperactivating and rewarding properties of ethanol across species. Flies, like humans, become inebriated, develop ethanol tolerance, ethanol preference, and ethanol reward associations, and they show signs of withdrawal. Many of these are adaptations to ethanol exposure that are forms of behavioral plasticity. How ethanol behavioral plasticity differs from non-addictive forms is key to understanding why some substances are abused. The goal of the research for this thesis was to ask if glial cells, like neuronal cells, promote behavioral plasticity induced by acute ethanol. Glial cells perform surprisingly diverse functions in the brain, including information transmission whose regulation is key to behavioral plasticity. A survey of the Drosophila glial types uncovered roles in ethanol tolerance for two types, the astrocytes that contact and regulate neuronal synapses, and the perineurial cells that form the outer surface of the blood-brain barrier. Dysregulation of glutamate homeostasis in astrocytes renders flies sensitive to acute inebriation and decreased ethanol tolerance. These ethanol phenotypes correlate with others that are early signatures of neurodegeneration caused by glutamate excitotoxicity. Perineurial cells show morphological change that correlated with reduced actin organization following acute ethanol exposure. This morphological change required Akap200, an adaptor protein that coordinates protein kinase A, protein kinase C, calcium, and actin at the perineurial plasma membrane. Loss of Akap200 either globally or specifically in the perineurium decreases ethanol tolerance development, as does disruption of many of the molecules that interact with Akap200. These Akap200 dependent functions appear to be occurring at the time of ethanol exposure. These findings indicate an active signaling role for the blood-brain barrier in the development of ethanol tolerance, and they imply that the barrier and neurons communicate to promote behavioral plasticity.