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5-羟色胺再摄取抑制剂（SSRIs）已成为治疗精神疾病的主流药物。基于它们在成人中的治疗效果，它们越来越多地用于儿童和青少年。然而，人们对SSRIs在年轻患者中的使用感到担忧，特别是由于自杀易感性增加的报道。最近，在小鼠模型中，在出生后早期时间范围（对应于第三个三个月至儿童期）长期给予SSRI已显示导致成年期焦虑增加，表明SSRI治疗幼龄小鼠具有焦虑原性。这表明发育中的大脑对SSRIs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对更临床相关的出生后时间范围（包括儿童晚期到青春期）的影响进行严格的检查。SSRIs可以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，如海马体，前额皮质和中脑边缘奖励回路。虽然BDNF水平在成年人中是稳定的，但在出生后的早期，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。在出生后的早期，proBDNF的表达最高，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可能发挥不同的作用，在突触的成熟和可塑性。从突触前位点释放的ProBDNF与p75结合以诱导长时程抑制（LTD），并潜在地降低棘密度和树突复杂性，而成熟的BDNF促进长时程增强（LTP）和增强的树突形态。我们推测，在儿童和青少年时期，SSRIs对BDNF的诱导可能导致神经元形态和功能的改变，以及皮质、海马和丘脑核之间的异常回路。这些研究利用BDNF检测的新技术进展，将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）扰乱BDNF水平，BDNF亚型转化，以及通过BDNF受体急性和成年期的信号传导;（B）诱导成人焦虑和抑郁表型。我们预测，出生后的发育变化的proBDNF和成熟的BDNF的比例可能是关键的差异影响的SSRI抗抑郁药调制结构和功能的神经可塑性，导致持久的异常行为反应的动物SSRIs治疗在关键的童年时期的脆弱性。 公共卫生相关性：基于其在成人中的治疗效果，选择性5-羟色胺再摄取抑制剂（SSRIs）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，早期生活SSRIs可能在以后的生活中产生有害的行为影响，如异常焦虑相关行为以及对压力的反应。我们的研究，利用新的技术进步，在小鼠模型中检测生长因子，BDNF，将使我们能够确定如何SSRIs，在儿童和青春期的脆弱时期交付，影响调节这一关键的生长因子，以调节结构和功能的神经可塑性，导致持久的异常行为反应SSRIs在关键的童年脆弱时期。

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.