Developmental origin of serotonin dysfunction in cortical map disruption

皮质图破坏中血清素功能障碍的发育起源

• 批准号: 9145791
• 负责人: JI Y SZE
• 金额: $ 44.63万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145791
• 关键词: Adult; Afferent Neurons; Anxiety; Architecture; Autistic Disorder; Axon; Behavior; Behavioral; Brain; Brain Stem; Brain region; Contralateral; Depression and Suicide; Development; Elderly; Emotions; Etiology; Extracellular Space; Fright; Functional disorder; Gene Expression; Genetic; Genetic Polymorphism; Genetic Programming; Glutamates; Goals; Health; Hippocampus (Brain); Lead; Life; Maps; Mental Depression; Mental disorders; Molecular; Mus; Mutant Strains Mice; Mutation; Neurons; Pathway interactions; Pattern; Play; Prefrontal Cortex; Presynaptic Terminals; Prevention; Process; Psychiatric therapeutic procedure; Risk; Role; Selective Serotonin Reuptake Inhibitor; Sensory; Serotonin; Shapes; Signal Transduction; Site; Synapses; Testing; Time; barrel cortex; cortex mapping; extracellular; hippocampal pyramidal neuron; mouse model; neural circuit; neuronal patterning; novel; postsynaptic; programs; receptor; research study; sensory cortex; serotonin transporter; spatiotemporal; synaptogenesis; theories; trait; uptake

 DESCRIPTION (provided by applicant): Dysregulation of serotonin (5-HT) signaling underscores the long-standing theory of circuit perturbations that lead to risks for mental disorders. 5-HT transporter SERT is a critical regulator of 5-HT signaling by limiting 5-HT availability at 5-HT receptors. SERT antagonists (e.g. SSRIs) are the first-line treatments for psychiatric traits. However, polymorphisms that reduce SERT gene expression/functionality are found to be associated with autism, depression, and increased anxiety, and confer structural and functional alterations in brain regions involved in emotion processing. The majority studies of SERT mechanisms focus on brainstem raphe neurons, which produce 5-HT and constitutively express SERT. We recently uncovered previously unknown differences between SERT mechanisms in developing and mature brain. Specifically, we identified a SERT function operating in a distinctly different set of neurons in defined brain regions during a specific time period of cortical maturation. In mice between E17 - P10, SERT is transiently expressed in glutamatergic thalamocortical axons (TCAs) projecting all the sensory cortices and in pyramidal neurons in the PFC and hippocampus. These neurons do not synthesize 5-HT but uptake extracellular 5-HT, termed "5-HT-absorbing neurons". To identify the role of SERT in 5-HT-absorbing neurons, we generated mutant mice with SERT expression disrupted in glutamatergic TCAs (SERTGluΔ), or in pyramidal neurons in the cortex (SERTCortexΔ), or in raphe 5-HT-producing neurons (SERTRapheΔ). Studies of SERTGluΔ and SERTRapheΔ mice revealed that SERT in 5-HT-absorbing TCAs, not SERT in raphe afferents, is a determinant of columnar patterning and dendritic architecture of the sensory cortex. We hypothesize that SERT expressed in 5-HT-absorbing axons regulates trophic 5-HT signals during circuit establishment, whereas SERT in raphe neuron axons assumes a critical role in regulating synaptic 5-HT in the mature cortex. We propose systematic genetic, anatomical and behavioral experiments investigating how spatiotemporal SERT expression in 5-HT-absorbing axons and SERT in raphe neuron afferents play out to influence cyto- and synapto-architecture in developing and mature cortex and behavior. We anticipate that altered developmental SERT mechanism is likely to define the origins of malfunction of the neural circuits that drive certaub features of te mental disorders, and illuminate the fundamental mechanisms of early life programming of behavior. By uncoupling SERT function in the developing and mature CNS, our studies will inform the cellular sites and timing of SERT expression that underscore the risks for developing mental disorders and that contribute to mental disorder treatments.

 描述（由申请人提供）：血清素 (5-HT) 信号传导失调强调了长期存在的电路扰动理论，该理论会导致精神障碍的风险。 5-HT 转运蛋白 SERT 通过限制 5-HT 受体上的 5-HT 可用性，是 5-HT 信号转导的关键调节剂。 SERT 拮抗剂（例如 SSRI）是治疗精神疾病的一线药物。然而，减少 SERT 基因表达/功能的多态性被发现与自闭症、抑郁症和焦虑增加有关，并导致涉及情绪处理的大脑区域发生结构和功能改变。大多数 SERT 机制的研究都集中在脑干中缝神经元上，这些神经元产生 5-HT 并组成型表达 SERT。我们最近发现了发育中大脑和成熟大脑中 SERT 机制之间以前未知的差异。具体来说，我们确定了在皮质成熟的特定时间段内特定大脑区域的一组明显不同的神经元中运行的 SERT 功能。在 E17 - P10 之间的小鼠中，SERT 在投射所有感觉皮层的谷氨酸丘脑皮质轴突 (TCA) 以及 PFC 和海马的锥体神经元中短暂表达。这些神经元不合成5-HT，但摄取细胞外5-HT，称为“5-HT吸收神经元”。为了确定 SERT 在吸收 5-HT 的神经元中的作用，我们生成了谷氨酸能 TCA (SERTGluΔ)、皮质锥体神经元 (SERTCortexΔ) 或中缝 5-HT 产生神经元 (SERTRapheΔ) 中 SERT 表达被破坏的突变小鼠。对 SERTGluΔ 和 SERTRapheΔ 小鼠的研究表明，5-HT 吸收 TCA 中的 SERT，而不是中缝传入神经中的 SERT，是感觉皮层柱状图案和树突结构的决定因素。我们假设在 5-HT 吸收轴突中表达的 SERT 在回路建立过程中调节营养性 5-HT 信号，而中缝神经元轴突中的 SERT 在调节成熟皮质中的突触 5-HT 中发挥关键作用。我们提出系统的遗传、解剖和行为实验，研究 5-HT 吸收轴突中的时空 SERT 表达和中缝神经元传入中的 SERT 如何影响发育和成熟皮质和行为中的细胞和突触结构。我们预计，改变的发育 SERT 机制可能会定义驱动精神障碍某些特征的神经回路故障的起源，并阐明早期生命编程行为的基本机制。通过解开发育中和成熟中枢神经系统中的 SERT 功能，我们的研究将告知 SERT 表达的细胞位点和时间，这强调了发生精神障碍的风险，并有助于精神障碍的治疗。

项目成果

Sex-biased effects on hippocampal circuit development by perinatal SERT expression in CA3 pyramidal neurons.

CA3 锥体神经元围产期 SERT 表达对海马回路发育的性别偏见影响。

• DOI: 10.1242/dev.200549
• 发表时间: 2022
• 期刊: Development (Cambridge, England)
• 作者: DeGregorio,Roberto;Subah,Galadu;Chan,JenniferC;Speranza,Luisa;Zhang,Xiaolei;Ramakrishnan,Aarthi;Shen,Li;Maze,Ian;Stanton,PatricK;Sze,JiY
• 通讯作者: Sze,JiY