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: 8442916
• 负责人: Xiang Cai
• 金额: $ 35.94万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442916
• 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; 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; Pathway interactions; Pharmaceutical Preparations; Phospho-Specific Antibodies; Phosphorylation; Physiological; Play; Process; Prosencephalon; Rattus; Receptor Activation; 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.

描述（由申请人提供）：血清素信号传导是抗抑郁药物的主要靶点，在精神疾病中可能失调。5-羟色胺能传入和5-羟色胺5-HT 1B受体集中在腔隙分子层（SLM），其中来自内嗅皮层的颞-氨（TA）通路的神经元能突触输入也终止。TA通路提供从皮层到CA 1锥体神经元的唯一直接输入，因此是感觉信息的主要来源。目的：确定5-HT 1B受体如何调节TA-CA 1突触传递，并确定这些过程在抑郁症中如何失调，以及如何通过慢性抗抑郁药治疗恢复。初步结果：5-HT 1B受体的激活增强了CA 1 SLM中由TA刺激而不是由Schaffer侧支刺激引起的兴奋性突触后电位（场EPSP和EPSP）。这种增强作用是由增加的突触后AMPA受体介导的传递介导的，并伴随着AMPA受体GluR 1在PKC/CaMKII Ser 831位点的磷酸化。5-HT 1B受体激活对TA-CA 1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，并被慢性抗抑郁药治疗阻断。具体目标：1.测试5-HT 1B受体诱导的增强和活性依赖性突触可塑性是否具有共同的信号传导机制，导致TA-CA 1突触处的AMPA受体插入。2.确定如何增强TA-CA 1突触传递的5-HT 1B受体增强后，慢性不可预测的压力。3.确定为什么在慢性抗抑郁药治疗后，5-HT 1B受体对TA-CA 1突触传递的增强作用不存在。4.在GluR 1 S831 A转基因小鼠中，当5-HT 1B受体被阻断时，或当阿托伐他汀诱导的增强作用不存在时，测试慢性抗抑郁治疗是否可以逆转抑郁症的行为体征，即快感缺乏。研究设计：我们将结合联合收割机电生理学技术，包括谷氨酸盐光解，和细胞生物学技术，例如用组成型活性和显性负性构建体转染、蛋白质印迹和生物素化测定，以研究5-HT 1B受体在取自对照动物和经历CUS和慢性抗抑郁治疗的动物的海马切片中的作用。结果：该项目将扩大我们对5-羟色胺生理作用的理解，并确定抑郁症是否部分源于参与认知和情感功能的多个大脑区域兴奋性突触传递强度的失调。更好地了解血清素的作用及其在压力下的变化将有助于改善抗抑郁治疗策略。