Astrocytic dysfunction in anxiety and depression during alcohol withdrawal Many alcohol dependent patients suffer from other co-occurring psychiatric disorders. Indeed, anxiety and depression, common symptoms of alcohol withdrawal, frequently co-occur and are important factors in the negative reinforcement leading to excessive alcohol drinking. The development of anxiety and depression upon prolonged alcohol exposures reflects synaptic adaptations that have a cellular, molecular, and structural basis. Evidently, astrocyte-neuron interaction plays an important role in alcohol withdrawal symptoms (AWS) such as anxiety and depression. Glutamate transporter type 1 (GLT1, as known as EAAT2 in human) is dominantly localized in astrocyte and responsible for glutamate homeostasis. Although emerging clinical and preclinical evidence has implicated the important role of GLT1 in anxiety, depression and alcohol drinking as well, however, it has remained largely unknown how GLT1 underlies the synaptic adaptations and the behavioral consequences cell-type or brain-region dependently. My preliminary data demonstrate that withdrawal from repeated alcohol exposure reduces the GLT1 expression in the brain region critical for regulation of emotion. While systemic applications of drugs that upregulate GLT1 expression and function ameliorate anxiety- and depressive-like behaviors induced by the alcohol withdrawal. Thus, I propose the overarching hypothesis: GLT1 is a critical regulator of comorbid anxiety and depression during alcohol withdrawal. To investigate this hypothesis, I will 1) examine how this tripartite synapse, especially the expression and function of GLT1 in brain, is adapted by withdrawal from repeated alcohol exposure and 2) determine the effects of cell-type and region specific manipulation of GLT1 in alcohol seeking and anxiety- and depressive-like behaviors. To achieve our goals, I will employ a combination of electrophysiological, pharmacological, optical, behavioral and transgenic approaches. These studies will elucidate the tripartite synaptic mechanisms and molecules that are adapted by alcohol withdrawal and be the initial step toward achievement of my long-term goal to identify a glutamatergic bio-signature of vulnerability and susceptibility in alcoholism and psychiatric disorders. The proposed research and career development plan, along with my mentor, advisory committee and the interdisciplinary approaches encouraged at Mayo Clinic College of Medicine, will provide the support and additional training necessary to become an independent investigator in an academic research environment.
Glutamate transporter 1 (GLT1) is involved in the regulation of glutamate homeostasis at tripartite synaptic events. These proposed studies will provide new mechanistic insights into how GLT1 is adapted during alcohol withdrawal and affects the comorbid anxiety and depression, leading to the development of new therapeutic approaches for alcohol use disorders.
