Long-term effects of binge drinking on astrocyte-synaptic interactions

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Operation Enduring Freedom in Afghanistan and Operation Iraqi Freedom (OEF/OIF) studies report that combat veterans are at increased risk for binge drinking and the development of alcohol use disorder (AUD). 38% of Army active duty members surveyed returning from OEF/OIF deployments between 2008 and 2011 reported binge drinking. Furthermore, veterans between the ages of 20 and 25 are 2.21 times more likely to binge drink and 2.24 times more likely to have an AUD than their peers aged 46 years or older, outlining the prevalence of alcohol abuse in the young veteran population. Importantly, more than 50% of males surveyed reported hazardous binge drinking even prior to deployment. Despite repeated binge drinking being associated with acute and long-term cognitive impairment and increased likelihood of developing AUD, the underlying mechanisms are not well understood. Studies using a rat model of binge drinking called chronic intermittent ethanol exposure (CIE) demonstrate long-term deficits in hippocampal neuronal structure, function, and behavior. We have shown that, coincident with changes in CA1 hippocampal neuronal circuit function, binge ethanol (EtOH) exposure results in chronic dysregulation of astrocyte-secreted signaling factors known to be involved in synaptic remodeling. Astrocytes tightly regulate synaptic activity and ion homeostasis through their perisynaptic astrocyte processes (PAPs), allowing for bi-directional communication through various contact-mediated and secreted signaling factors that modulate synaptic transmission. In addition, the behavioral relevance of astrocyte/synaptic communication is beginning to emerge through exciting new advances showing astrocytes to be involved in behavioral resiliency, fear learning, and contributing to working memory deficits following drug exposure. Our current data demonstrate that EtOH-induced persistence of immature dendritic spines (i.e. sites of excitatory synaptic input) is spatiotemporally linked with PAP-synaptic decoupling. We predict that disruption of PAP proximity to synapses compromises the ability of astrocytes to regulate synaptic homeostasis. Therefore, the overall objective of this application is to elucidate how EtOH-induced disruption of astrocyte function and PAP-synaptic coupling contributes to long-term changes in synaptic networks. Achieving this objective will allow us to reach our long-term goal, which is to identify the cellular and molecular mechanisms that may inform novel treatments for the prevention and reversal of synaptic dysfunction and the emergence of AUD after repeated binge EtOH exposure. Our central hypothesis is that repeated binge EtOH exposure triggers aberrant astrocyte signaling and disruption of PAP-synaptic proximity that drive lasting deficits in synaptic structure and homeostasis. The rationale behind this project is that understanding how disruption of astrocyte function and PAP-synaptic communication occur will contribute key insight into the mechanisms underlying synaptic dysfunction following binge EtOH exposure. The proposed research is significant since successful completion will result in the identification of non-neuronal processes critical for the prevention and reversal of neuronal circuit remodeling following binge ethanol exposure. An interdisciplinary team of investigators with expertise in the field of alcohol, astrocytes, serial section electron microscopy, and electrophysiology will conduct this innovative project.