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）：此申请应解决广泛的挑战领域（15）转化科学和特定挑战主题，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疗法。根据他们在成年人中的治疗作用，他们越来越在儿童和青少年中处方。但是，由于有报道称自杀的易感性增加，人们特别关心在年轻患者中使用SSRI。最近，在小鼠模型中，在产后早期的慢性SSRI给药，对应于三个月至童年，已证明会导致成年后的焦虑增加，这表明年轻小鼠的SSRI治疗是焦虑的。这表明发育中的大脑对SSRI的反应与成人大脑的反应非常不同。但是，在这些模型系统中尚未进行严格检查SSRI对临床相关的后时间范围，包括至少青春期的童年后期。 SSRI可以减轻成年后焦虑的一种重要机制是通过在关键大脑区域（例如海马，前额叶皮层和中唇奖励回路）诱导BDNF水平。尽管BDNF水平在成年人中是稳定的，但在产后早期生活中，BDNF表达是峰值的，并且在动态调节中可能是由于其在神经回路成熟中的关键作用。 BDNF存在于2种同工型中，一个最初合成的前体，probDNF和较小的成熟BDNF形式。 probDNF的表达在产后早期的早期寿命中最高，而成年的成年BDNF则主要是成年人。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起不同的作用。从突触前部位释放的ProbDNF与p75结合以诱导长期抑郁（LTD），并有可能降低脊柱密度和树突的复杂性，而成熟的BDNF促进长期增强（LTP）并增强了树突状态。我们假设SSRI在儿童期和青春期对BDNF的诱导可能导致神经元的形态和功能改变，并且在皮质，海马和Accumbens之间的异常电路以及异常的回路。这些研究利用BDNF检测的新技术进步将使我们能够确定在童年和青春期期间脆弱时期交付的SSRI（a）perturbs bdnf水平，bdnf同工型转换，以及通过BDNF受体发出信号传导（b）诱导成人焦虑和抑郁表型。我们预测，probDNF和成熟BDNF比的产后发育变化可能是SSRI抗抑郁药对调节结构和功能性神经可塑性调节的关键差异效应，从而导致在关键的脆弱性儿童期间用SSRIS治疗的动物持久的异常行为反应。 公共卫生相关性：根据他们在成年人的治疗作用，选择性5-羟色胺再摄取抑制剂（SSRIS）越来越多地在儿童和青少年中处方。但是，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，早期的生命SSRI可以在以后的生活中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。在小鼠模型中，我们利用新的技术进步BDNF在检测生长因子时的研究将使我们能够确定在儿童期和青春期期间脆弱时期交付的SSRI会影响对这种关键生长因子的调节，从而调节结构性和功能性神经可变性，从而导致对较长的sssris ssris ssris的持久性神经形象，从而在较大的儿童时期内差异。