Stress, Depression, Serotonin, and Plasticity of Excitatory Transmission

压力、抑郁、血清素和兴奋性传递的可塑性

• 批准号: 7888851
• 负责人: Xiang Cai
• 金额: $ 37.78万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888851
• 关键词: AMPA Receptors; Alcohol or Other Drugs use; Anhedonia; Animal Model; Animals; Antidepressive Agents; Apical; Behavioral; Behavioral Symptoms; Biological; Biological Assay; Biotinylation; Brain; Brain region; Calcium/calmodulin-dependent protein kinase; Cell surface; Cells; Chemosensitization; Chronic; Chronic stress; Cognitive; Communication; Control Animal; Data; Dendrites; Distal; Dominant-Negative Mutation; Down-Regulation; Emotional; Emotions; Excitatory Postsynaptic Potentials; Experimental Designs; Functional disorder; Glutamate Receptor; Glutamates; Hippocampus (Brain); Human; Immunoblotting; Lead; Learning; Long-Term Potentiation; Mediating; Memory; Mental Depression; Mental disorders; Modeling; Outcome; Pathway interactions; Pharmaceutical Preparations; Phospho-Specific Antibodies; Phosphorylation; Physiological; Play; Process; Prosencephalon; Rattus; Receptor Activation; Research Design; Role; Second Messenger Systems; Sensory; Serotonin; Serotonin Receptor 5-HT1B; Signal Pathway; Signal Transduction; Site; Slice; Source; Stress; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Therapeutic Effect; Transfection; Transgenic Mice; Up-Regulation; Western Blotting; base; behavior measurement; calmodulin-dependent protein kinase II; density; design; entorhinal cortex; hippocampal pyramidal neuron; improved; information processing; innovation; multidisciplinary; novel; photolysis; postsynaptic; public health relevance; receptor; research study; response; second messenger; social; social stress; synaptic function; transmission process; treatment strategy

DESCRIPTION (provided by applicant): Serotonin signaling is a primary target of antidepressant medication, and may be dysregulated in psychiatric diseases. Serotonergic afferents and serotonin 5-HT1B receptors to the hippocampus are concentrated in stratum lacunosum-moleculare (SLM), where glutamatergic synaptic input from the entorhinal cortex, the temporo-ammonic (TA) pathway, also terminates. The TA pathway provides the only direct input to CA1 pyramidal neurons from the cortex and is thus a main source of sensory information. OBJECTIVE: to determine how 5-HT1B receptors regulate TA-CA1 synaptic transmission and determine how these processes are dysregulated in depression and restored by chronic antidepressant treatment. PRELIMINARY RESULTS: activation of 5-HT1B receptors potentiates excitatory postsynaptic potentials (field EPSPs and EPSPs) elicited by TA stimulation in CA1 SLM, but not by Schaffer collateral stimulation. The potentiation is mediated by increased postsynaptic AMPA receptor mediated transmission and accompanied by phosphorylation of the AMPA receptor GluR1 at the PKC/CaMKII Ser831 site. The effects of 5-HT1B receptor activation on TA-CA1 synaptic transmission are enhanced in rats subjected to chronic unpredictable stress (CUS), an accepted animal model of depression, and blocked by chronic antidepressant treatment. SPECIFIC AIMS: 1. Test whether 5-HT1B receptor-induced potentiation and activity-dependent synaptic plasticity share common signaling mechanisms that lead to AMPA receptor insertion at TA-CA1 synapses. 2. Determine how potentiation of TA-CA1 synaptic transmission by 5-HT1B receptors is enhanced after chronic unpredictable stress. 3. Determine why potentiation of TA-CA1 synaptic transmission by 5-HT1B receptors is absent after chronic antidepressant treatment. 4. Test whether chronic antidepressant treatment can reverse a behavioral sign of depression, anhedonia, when 5-HT1B receptors are blocked pharmacologically or when serotonin-induced potentiation is absent in GluR1 S831A transgenic mice. RESEARCH DESIGN: we will combine electrophysiological techniques, including glutamate photolysis, with cell biological techniques such as transfection with constitutively active and dominant negative constructs, western blotting, and biotinylation assays, to investigate the actions of 5-HT1B receptors in hippocampal slices taken from control animals and animals subjected to CUS and chronic antidepressant treatment. OUTCOMES: The proposed project will expand our understanding of the physiological actions of serotonin and determine whether depression results, in part, from a dysregulation of the strength of excitatory synaptic transmission in multiple brain regions involved in cognitive and emotional function. A better understanding of serotonin actions and their alteration by stress will lead to improved antidepressant treatment strategies. PUBLIC HEALTH RELEVANCE: Depression and other forms of mental illness are treated with drugs that act on a specific communication system in the brain that uses the substance serotonin. The normal function of this system is not well understood. Our experiments are designed to better understand the role played by this system in information processing in the healthy brain and how it may malfunction in mental illness.

描述（由申请人提供）：血清素信号是抗抑郁药物的主要靶点，在精神疾病中可能失调。海马的5-羟色胺能传入和5-羟色胺5-HT1B受体集中在空隙层-分子（SLM）中，在那里，来自内嗅皮层的谷氨酸能突触输入，即颞氨（TA）通路也终止。TA通路从皮层向CA1锥体神经元提供唯一的直接输入，因此是感觉信息的主要来源。目的：研究5-HT1B受体如何调节TA-CA1突触传递，以及这些过程在抑郁症中如何失调并通过慢性抗抑郁药物治疗得以恢复。初步结果：在CA1 SLM中，5-HT1B受体的激活增强了TA刺激引起的兴奋性突触后电位（EPSPs和EPSPs场），而Schaffer侧支刺激则没有。这种增强是通过增加突触后AMPA受体介导的传递介导的，并伴随着AMPA受体GluR1在PKC/CaMKII Ser831位点的磷酸化。5-HT1B受体激活对TA-CA1突触传递的影响在慢性不可预测应激（CUS）大鼠（一种公认的抑郁症动物模型）中增强，并被慢性抗抑郁药物治疗阻断。具体目标：1；测试5-HT1B受体诱导的增强和活动依赖性突触可塑性是否具有导致AMPA受体插入TA-CA1突触的共同信号机制。2. 确定慢性不可预测应激后5-HT1B受体对TA-CA1突触传递的增强是如何增强的。3. 确定为什么5-HT1B受体在慢性抗抑郁治疗后缺乏TA-CA1突触传递的增强。4. 测试在GluR1 S831A转基因小鼠中，当5-HT1B受体被药理学阻断或血清素诱导的增强缺失时，慢性抗抑郁治疗是否可以逆转抑郁、快感缺乏的行为迹象。研究设计：我们将结合电生理技术（包括谷氨酸光解）和细胞生物学技术（如组成活性和显性阴性结构转染、western blotting和生物素化测定），研究5-HT1B受体在对照动物和接受CUS和慢性抗抑郁治疗的动物海马切片中的作用。结果：拟议的项目将扩大我们对血清素生理作用的理解，并确定抑郁症的部分原因是否来自涉及认知和情绪功能的多个大脑区域的兴奋性突触传递强度失调。更好地了解血清素的作用及其在压力下的改变将有助于改善抗抑郁治疗策略。