Molecular Mechanisms of SSRI Action in Childhood and Adolescence

SSRI 在儿童和青少年时期作用的分子机制

• 批准号: 7938928
• 负责人: Francis Sang Yong Lee
• 金额: $ 50万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938928
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; Animal Model; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Area; Attenuated; Behavior; Behavioral; Binding; Binding Sites; Biological Models; Brain; Brain region; Brain-Derived Neurotrophic Factor; Child; Childhood; Chronic; Detection; Development; Elements; Epitopes; Fluoxetine; Growth; Growth Factor; Hippocampus (Brain); Knock-in Mouse; Late Effects; Lead; Life; Long-Term Depression; Long-Term Effects; Long-Term Potentiation; Longitudinal Studies; Mainstreaming; Measures; Mental Depression; Mental disorders; Molecular; Morphology; Mus; Neuronal Differentiation; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Nucleus Accumbens; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Predisposition; Prefrontal Cortex; Process; Protein Isoforms; Regulation; Reporting; Rewards; Role; Secretory Vesicles; Selective Serotonin Reuptake Inhibitor; Signal Transduction; Site; Sorting - Cell Movement; Stress; Suicide; Synapses; Synaptic Cleft; Synaptic Transmission; Therapeutic Effect; Time; Translational Research; Vertebral column; base; clinically relevant; density; depressive symptoms; mouse model; neural circuit; neurodevelopment; postnatal; presynaptic; promoter; public health relevance; receptor; response; tool; transcriptional coactivator p75; treatment response

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- MH-101: Effect of psychotropic medications on neurodevelopment and behavior in animal models. Selective serotonin reuptake inhibitors (SSRIs) have become the mainstream therapy in psychiatric diseases. Based on their therapeutic effect in adults, they are increasingly prescribed in children and adolescents. However, there is a concern about the use of SSRIs in young patients, in particular, due to reports of increased susceptibility to suicide. Recently, in mouse models, chronic SSRI administration at an early postnatal time frame, corresponding to 3rd trimester to childhood has been shown to lead to increased anxiety in adulthood, suggesting that SSRI treatment in young mice is anxiogenic. This suggests that the developing brain responds to SSRIs very differently than the adult brain. However, rigorous examination of the effects of SSRIs on more clinically relevant postnatal time frames, encompassing late childhood through adolescence, have not been performed in these model systems. One important mechanism by which SSRIs may attenuate anxiety in adulthood is through the induction of BDNF levels in critical brain regions, such as the hippocampus, prefrontal cortex, and mesolimbic reward circuit. Although BDNF levels are stable in adults, in early postnatal life, BDNF expression is peaking and is dynamically regulated presumably due to its critical role in neural circuit maturation. BDNF exists in 2 isoforms, an initially synthesized precursor, proBDNF, and a smaller mature BDNF form. Expression of proBDNF is highest in early postnatal life, whereas mature BDNF predominates in adults. Recent studies suggest that proBDNF and mature BDNF may play divergent roles in synaptic maturation and plasticity. ProBDNF released from presynaptic sites binds to p75 to induce long term depression (LTD), and to potentially reduce spine density and dendritic complexity, whereas mature BDNF promotes long term potentiation (LTP) and enhanced dendritic morphology. We hypothesize that induction of BDNF by SSRIs in childhood and adolescence may lead to altered neuronal morphology and function, and abnormal circuitry between cortex, hippocampus, and nucleus accumbens. These studies, utilizing new technical advances in BDNF detection will allow us to determine how SSRIs, delivered during vulnerable periods during childhood and adolescence (a) perturbs BDNF levels, BDNF isoform conversion, and signaling through BDNF receptors acutely, and in adulthood; (b) induce adult anxiety and depressive phenotypes. We predict that the postnatal developmental changes in proBDNF and mature BDNF ratios may underlie critical differential effects of SSRI antidepressants on modulating structural and functional neural plasticity, leading to long-lasting abnormal behavioral responses in animals treated with SSRIs during critical childhood periods of vulnerability. PUBLIC HEALTH RELEVANCE: Based on their therapeutic effect in adults, selective serotonin reuptake inhibitors (SSRIs) are increasingly being prescribed in children and adolescents. However, there is a concern about the longterm consequences of these medications. Importantly, several animal model studies have shown that early life SSRIs can have deleterious behavioral effects later in life such as abnormal anxiety-related behaviors, as well as responses to stress. Our studies, utilizing new technical advances in detection of the growth factor, BDNF, in mouse models will allow us to determine how SSRIs, delivered during vulnerable periods during childhood and adolescence, affects regulation of this critical growth factor to modulate structural and functional neural plasticity, leading to long-lasting abnormal behavioral responses to SSRIs during critical childhood periods of vulnerability.

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和具体挑战主题，15-MH-101：精神药物对动物模型中神经发育和行为的影响。选择性5-羟色胺再摄取抑制剂（SSRIs）已成为精神疾病的主流治疗方法。基于其对成人的治疗效果，它们越来越多地用于儿童和青少年。然而，人们对年轻患者使用 SSRI 存在担忧，特别是因为有报道称年轻患者自杀的可能性增加。最近，在小鼠模型中，在出生后早期（即妊娠第 3 个月至儿童期）长期服用 SSRI 已被证明会导致成年期焦虑增加，这表明 SSRI 治疗对幼鼠具有致焦虑作用。这表明发育中的大脑对 SSRI 的反应与成人大脑非常不同。然而，在这些模型系统中尚未对 SSRIs 对更具临床相关性的产后时间范围（涵盖童年晚期到青春期）的影响进行严格检查。 SSRIs 减轻成年期焦虑的一种重要机制是通过诱导关键大脑区域（如海马体、前额皮质和中脑边缘奖励回路）的 BDNF 水平。尽管 BDNF 水平在成人中稳定，但在出生后早期，BDNF 表达达到峰值，并且可能由于其在神经回路成熟中的关键作用而受到动态调节。 BDNF 有 2 种亚型，一种是最初合成的前体，即 proBDNF，另一种是较小的成熟 BDNF 形式。 proBDNF 的表达在出生后早期最高，而成熟的 BDNF 在成人中占主导地位。最近的研究表明，proBDNF 和成熟的 BDNF 可能在突触成熟和可塑性中发挥不同的作用。从突触前位点释放的 ProBDNF 与 p75 结合，诱导长期抑制 (LTD)，并可能降低树突棘密度和树突复杂性，而成熟的 BDNF 则促进长期增强 (LTP) 和增强树突形态。我们假设儿童期和青少年期 SSRIs 诱导 BDNF 可能导致神经元形态和功能改变，以及皮质、海马和伏核之间的异常回路。这些研究利用 BDNF 检测方面的新技术进展，使我们能够确定在儿童和青春期的脆弱时期提供的 SSRIs 如何（a）在成年期急剧扰乱 BDNF 水平、BDNF 亚型转换和通过 BDNF 受体的信号传导； (b) 诱发成人焦虑和抑郁表型。我们预测，proBDNF 和成熟 BDNF 比率的出生后发育变化可能是 SSRI 抗抑郁药对调节结构和功能神经可塑性的关键差异效应的基础，导致接受 SSRI 治疗的动物在脆弱的关键童年时期出现长期持续的异常行为反应。 公共健康相关性：基于其对成人的治疗效果，选择性血清素再摄取抑制剂（SSRI）越来越多地用于儿童和青少年。然而，人们担心这些药物的长期后果。重要的是，一些动物模型研究表明，生命早期的 SSRIs 可能会对以后的生活产生有害的行为影响，例如异常的焦虑相关行为以及对压力的反应。我们的研究利用新技术在小鼠模型中检测生长因子 BDNF，这将使我们能够确定在儿童期和青春期脆弱期施用的 SSRIs 如何影响这一关键生长因子的调节，从而调节结构和功能神经可塑性，从而导致在儿童期的关键脆弱期对 SSRIs 产生持久的异常行为反应。