Ethanol and Plasticity of Tripartite Synapses

乙醇与三联突触的可塑性

• 批准号: 7941067
• 负责人: L Judson Chandler
• 金额: $ 18.25万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941067
• 关键词: Actins; Acute; Affect; Alcohol dependence; Alcohol-Related Disorders; Alcoholism; Alcohols; Alteplase; Amygdaloid structure; Astrocytes; Behavioral; Brain; Breathing; Cells; Chronic; Communication; Coupled; Data; Dendritic Spines; Dependence; Dyes; Ethanol; Extracellular Matrix; Extracellular Matrix Degradation; Glutamates; Hippocampus (Brain); Image; Image Analysis; In Vitro; Infection; Lead; Learning; Life; Measures; Memory; Metabolic; Metalloproteases; Modeling; Modification; Morphology; Mus; N-Methyl-D-Aspartate Receptors; Neuroglia; Neurons; Peptide Hydrolases; Play; Positioning Attribute; Presynaptic Terminals; Procedures; Process; Proteins; Publishing; Regulation; Role; Series; Signal Pathway; Site; Slice; Structure; Synapses; Synaptic plasticity; Testing; Three-dimensional analysis; Time; Vertebral column; Withdrawal; alcohol abuse therapy; alcohol craving; alcohol exposure; alcohol seeking behavior; cell preparation; density; effective therapy; extracellular; hippocampal pyramidal neuron; in vivo; neuronal excitability; neurotrophic factor; new therapeutic target; novel; novel strategies; postsynaptic; public health relevance; response; vapor

DESCRIPTION (provided by applicant): It is now widely recognized that astrocytes (astroglia) play a central role in controlling excitability of neurons and contribute to the cellular mechanisms associated with learning and the formation of new memories. The plasticity of learning and memory formation involve changes in dendritic spines at glutamatergic synapses on neurons, and astrocytes form tripartite synaptic structures at a majority of mature spines. Astrocytes regulate extracellular glutamate levels and secrete gliotransmitters, neurotrophic factors, and proteases that affect the function and structure of the tripartite synaptic structure. It is this close physical localization of astroglia with glutamatergic synapses that places the astroglial process in a position to control neuronal excitability and synaptic plasticity. Moreover, the presence of astrocytes at glutamatergic synapses modulated the structure of the spine and controls NMDA receptor-dependent metaplasticity of hippocampal CA1 pyramidal neurons. It is well- established that chronic exposure of alcohol to hippocampal neurons increases the number of NMDA receptors at glutamatergic synapses, and it has also been suggested that this increase may promote actin-dependent increases in the size of the spine. These changes are suggested to contribute to alcohol dependence and tolerance. However, it is unknown what role astrocytes play in regulating the structural and functional plasticity of glutamatergic synapses associated with chronic alcohol exposure and withdrawal. In this exploratory R21 application, we will examine chronic alcohol-induced structural remodeling of the tripartite synapse. The over-arching hypothesis is that alcohol exposure induces the release of certain proteases from both neurons and astroglia that control spine-astroglial structural and functional plasticity. Three specific aims are proposed that will test our proposed model of alcohol- induced plasticity of tripartite synaptic structure: Aim 1 will test the hypothesis that acute and chronic in-vitro alcohol exposure alters the structural dynamics of the tripartite synapse in a live-cell preparation; Aim 2 will test the hypothesis that chronic in-vivo ethanol exposure alters the morphology and density of tripartite synapses; and Aim 3 will test the hypothesis that ethanol-induced structural plasticity of the tripartite synapse is associated with the release of proteases that act upon the synaptic extracellular matrix. These studies will utilize novel diolistic dye loading procedures and lentiviral infection of fluorescent proteins to visualize tripartite synaptic structures coupled with confocal imaging and sophisticated 3D-image analysis of alcohol-induced alterations in spine-astrocyte structures. The broad, long term objectives of this proposal are to determine if astrocytes contribute to alcohol-induced plasticity of glutamatergic synapses and whether astrocytes can be identified as a novel therapeutic target for the treatment of alcohol abuse and dependence. PUBLIC HEALTH RELEVANCE: Alcoholism is characterized by craving for alcohol and compulsive alcohol-seeking behavior. Thus, determining the processes by which alcohol exposure leads to aberrant and inappropriate synaptic connections of the brain may lead to novel approaches to effective treatments of alcoholism and alcohol related disorders.

描述（由申请人提供）：现在已广泛认识到星形胶质细胞（星形胶质细胞）在控制神经元的兴奋性方面起着核心作用，并有助于与学习和形成新记忆有关的细胞机制。学习和记忆形成的可塑性涉及在神经元上谷氨酸能突触的树突状刺发生的变化，而星形胶质细胞在大多数成熟的棘突上形成三方突触结构。星形胶质细胞调节细胞外谷氨酸水平，并分泌神经胶质器，神经营养因子以及影响三方突触结构功能和结构的蛋白酶。正是这种与谷氨酸能突触的星形胶质细胞的物理定位置于控制神经元兴奋性和突触可塑性的位置。此外，谷氨酸能突触的星形胶质细胞的存在调节了脊柱的结构，并控制了海马CA1锥体神经元的NMDA受体依赖性化塑性。据确定的是，酒精慢性暴露于海马神经元增加了谷氨酸能突触中NMDA受体的数量，并且还建议这种增加可能促进脊椎依赖性肌蛋白的依赖性增加。这些变化被认为有助于酒精依赖性和耐受性。然而，尚不清楚星形胶质细胞在调节与慢性酒精暴露和戒断有关的谷氨酸能突触的结构和功能可塑性中的作用。在此探索性R21应用中，我们将检查三方突触的慢性酒精诱导的结构重塑。总结的假设是，酒精暴露诱导了控制脊柱 - 腹膜结构和功能可塑性的神经元和星形胶质细胞的某些蛋白酶的释放。提出了三个具体目的，该目标将测试我们提出的酒精诱导的三方突触结构的可塑性：AIM 1将检验以下假设：急性和慢性体内酒精暴露会改变三方突触的结构动力学在活细胞制备中的结构动力学； AIM 2将检验以下假设：慢性体内乙醇暴露会改变三方突触的形态和密度。 AIM 3将检验以下假设：乙醇诱导的三方突触的结构可塑性与作用于突触细胞外基质的蛋白酶的释放有关。这些研究将利用荧光蛋白的新型二元染料载荷和慢病毒感染来可视化三方突触结构，以及共焦成像和葡萄酒诱导的脊柱腹腔腹腔细胞结构变化的复杂3D图像分析。该提案的广泛，长期的目标是确定星形胶质细胞是否有助于酒精诱导的谷氨酸能突触可塑性，以及是否可以将星形胶质细胞确定为治疗酒精滥用和依赖性的新型治疗靶标。 公共卫生相关性：酒精中毒的特征是渴望酒精和强迫性饮酒行为。因此，确定酒精暴露导致大脑的异常和不适当的突触连接的过程可能会导致有效治疗酒精中毒和酒精相关疾病的新方法。