Developmental origin of serotonin dysfunction in cortical map disruption

 描述(由申请人提供)：5-羟色胺(5-羟色胺)信号的失调强调了长期存在的电路扰动导致精神障碍风险的理论。5-羟色胺转运体SERT通过限制5-羟色胺受体上5-羟色胺的可获得性，是5-羟色胺信号转导的重要调节因子。SERT拮抗剂(例如SSRI)是治疗精神症状的一线药物。然而，降低SERT基因表达/功能的多态被发现与自闭症、抑郁症和增加的焦虑有关，并导致参与情绪处理的大脑区域的结构和功能变化。对SERT机制的研究大多集中在脑干中缝神经元，这些神经元产生5-羟色胺并结构性地表达SERT。我们最近发现了发育中的大脑和成熟的大脑中SERT机制之间的未知差异。具体地说，我们确定了在特定的皮质成熟时间段内，SERT功能在特定大脑区域的一组明显不同的神经元中起作用。在E17-P10的小鼠中，SERT在投射所有感觉皮质的谷氨酸能丘脑皮质轴突(TCA)以及在PFC和海马区的锥体神经元中瞬时表达。这些神经元不合成5-羟色胺，但摄取细胞外的5-羟色胺，称为“5-羟色胺吸收神经元”。为了确定SERT在5-羟色胺吸收神经元中的作用，我们产生了在谷氨酸能TCA(SERTGluΔ)、皮质锥体神经元(SERTCortexΔ)或中缝5-HT产生神经元(SERTRaphΔ)中SERT表达中断的突变小鼠。对SERTGluΔ和SERTRapheΔ小鼠的研究表明，5-羟色胺吸收的TCA中的SERT，而不是中缝传入中的SERT，是感觉皮质柱状图案和树突结构的决定因素。我们推测，SERT在5-羟色胺吸收轴突中的表达在回路建立过程中调节营养的5-羟色胺信号，而在中缝神经元轴突中的SERT在调节成熟皮质中突触的5-羟色胺起关键作用。我们提出了系统的遗传学、解剖学和行为学实验，研究5-羟色胺吸收轴突的时空SERT表达和中缝神经元传入的SERT如何影响发育和成熟皮质和行为的细胞和突触结构。我们预计，改变的发育SERT机制可能确定驱动某些精神障碍特征的神经回路故障的根源，并阐明早期行为生命编程的基本机制。通过解偶联SERT在发育和成熟的中枢神经系统中的功能，我们的研究将告知SERT表达的细胞位置和时间，强调发生精神障碍的风险，并有助于精神障碍的治疗。

 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.