Molecular Mechanisms of SSRI Action in Childhood and Adolescence

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15- MH-101：精神药物对动物模型中神经发育和行为的影响。选择性血清素再摄取抑制剂（SSRIs）已成为治疗精神疾病的主流药物。基于它们对成人的治疗效果，它们越来越多地被用于儿童和青少年。然而，对于年轻患者使用ssri类药物，尤其是自杀易感性增加的报告，值得关注。最近，在小鼠模型中，在出生后早期，即妊娠晚期至儿童期，长期服用SSRI会导致成年后焦虑增加，这表明SSRI治疗对年轻小鼠具有焦虑性。这表明，发育中的大脑对ssri类药物的反应与成人大脑非常不同。然而，在这些模型系统中，还没有对SSRIs对临床相关的产后时间框架（包括儿童期晚期到青春期）的影响进行严格的检查。SSRIs减轻成年期焦虑的一个重要机制是通过诱导关键大脑区域的BDNF水平，如海马、前额叶皮层和中脑边缘奖励回路。虽然BDNF水平在成人中是稳定的，但在出生后早期，BDNF的表达达到峰值，并受到动态调节，这可能是由于其在神经回路成熟中的关键作用。BDNF有两种亚型，一种是最初合成的前体proBDNF，另一种是较小的成熟BDNF。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。从突触前释放的ProBDNF与p75结合诱导长期抑制（LTD），并可能降低脊柱密度和树突复杂性，而成熟的BDNF促进长期增强（LTP）和增强树突形态。我们假设SSRIs在儿童和青少年时期诱导BDNF可能导致神经元形态和功能的改变，以及皮层、海马和伏隔核之间的异常电路。这些研究利用了BDNF检测的新技术进展，将使我们能够确定SSRIs在儿童和青少年的脆弱时期是如何(a)扰乱BDNF水平、BDNF亚型转化和通过BDNF受体的信号传导，以及在成年期；(b)诱导成人焦虑和抑郁表型。我们预测，产后proBDNF和成熟BDNF比例的发育变化可能是SSRI抗抑郁药在调节结构和功能神经可塑性方面的关键差异效应的基础，导致SSRIs治疗动物在儿童期脆弱的关键时期出现持久的异常行为反应。

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.