Stress, Depression, Serotonin, and Plasticity of Excitatory Transmission

描述(申请人提供)：5-羟色胺信号是抗抑郁药物的主要靶点，在精神疾病中可能是调节失调的。5-羟色胺能传入和5-羟色胺5-HT1B受体集中在腔隙分子层(SLM)，内嗅皮层的谷氨酸能突触输入也在此终止，即临时氨化(TA)通路。TA通路提供了皮层对CA1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：探讨5-HT1B受体对TA-CA1突触传递的调节作用，以及这些过程在抑郁症中的失调和慢性抗抑郁药物治疗后的恢复。初步结果：激活5-HT1B受体可增强TA刺激诱发的CA1SLM兴奋性突触后电位(场EPSP和EPSPS)，但不能增强Schaffer侧支刺激引起的兴奋性突触后电位(场EPSP和EPSPS)。这种增强是由突触后AMPA受体介导的传递增加所介导的，并伴随着PKC/CaMKII Ser831位点上AMPA受体GluR1的磷酸化。在慢性不可预测应激(CUS)的大鼠中，5-HT1B受体激活对TA-CA1突触传递的影响增强，CUS是公认的抑郁症动物模型，并被慢性抗抑郁药物治疗阻断。具体目的：1.检测5-HT1B受体诱导的突触增强和活性依赖性突触可塑性是否具有共同的信号机制，导致AMPA受体插入TA-CA1突触。2.确定慢性不可预知应激后，5-HT1B受体对TA-CA1突触传递的增强作用。3.确定慢性抗抑郁药物治疗后，5-HT1B受体不能增强TA-CA1突触传递的原因。4.在GluR1 S831a转基因小鼠中，测试当5-HT1B受体被药物阻断或5-羟色胺诱导的增强缺失时，慢性抗抑郁治疗是否可以逆转抑郁的行为症状-快感缺乏。研究设计：我们将结合电生理技术，包括谷氨酸光解技术，以及细胞生物学技术，如结构性活性和显性负性结构的转染，蛋白质印迹和生物素化试验，研究从对照组动物和慢性抗抑郁药物治疗的动物海马片中5-HT1B受体的作用。结果：拟议的项目将扩大我们对5-羟色胺的生理作用的理解，并确定抑郁症是否在一定程度上是由于涉及认知和情绪功能的多个大脑区域兴奋性突触传递强度的失调造成的。更好地了解5-羟色胺的作用和它们在应激中的变化将导致改进的抗抑郁治疗策略。

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.