Molecular Mechanisms of SSRI Action in Childhood and Adolescence

描述(申请人提供)：本申请涉及广泛的挑战领域(15)翻译科学和具体的挑战主题，15-MH-101：在动物模型中精神药物对神经发育和行为的影响。选择性5-羟色胺再摄取抑制剂(SSRIs)已成为精神疾病治疗的主流。基于它们对成人的疗效，它们越来越多地被开给儿童和青少年。然而，人们对在年轻患者中使用SSRI感到担忧，特别是因为有报道称，自杀易感性增加。最近，在小鼠模型中，在出生后早期长期给予SSRI，对应于妊娠晚期到儿童，已被证明会导致成年后焦虑增加，这表明SSRI在年轻小鼠中的治疗是焦虑性的。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对更具临床意义的出生后时间范围(包括儿童后期到青春期)的影响进行严格检查。SSRI可以减轻成年后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、前额叶皮质和中脑边缘奖赏回路。虽然BDNF在成人中的水平是稳定的，但在出生后的早期，BDNF的表达处于峰值，并受到动态调节，这可能是因为它在神经回路成熟中发挥了关键作用。BDNF以两种不同的形式存在，一种是最初合成的前体proBDNF，另一种是较小的成熟BDNF形式。ProBDNF在出生后早期的表达最高，而成熟的BDNF在成年后表达最多。最近的研究表明，ProBDNF和成熟的BDNF在突触成熟和可塑性中可能发挥着不同的作用。从突触前部位释放的ProBDNF与p75结合，诱导长期抑制(LTD)，并潜在地降低棘突密度和树突复杂性，而成熟的BDNF促进长时程增强(LTP)和增强树突形态。我们推测，在儿童和青春期，SSRI诱导BDNF可能导致神经元形态和功能的改变，以及皮质、海马和伏隔核之间的异常回路。这些研究，利用BDNF检测的新技术进步，将使我们能够确定在儿童和青少年时期的脆弱时期提供的SSRI是如何扰乱BDNF水平，BDNF亚型转换，并在成年后通过BDNF受体发出信号的；(B)诱导成人焦虑和抑郁表型。我们预测，ProBDNF和成熟BDNF比率在出生后的发育变化可能是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，导致在关键的儿童期脆弱时期接受SSRI治疗的动物出现长期的异常行为反应。 公共卫生相关性：基于对成人的治疗效果，选择性5-羟色胺再摄取抑制剂(SSRI)正越来越多地被开给儿童和青少年。然而，人们对这些药物的长期后果感到担忧。重要的是，几项动物模型研究表明，早期SSRI可能会在晚年产生有害的行为影响，如与焦虑相关的异常行为，以及对压力的反应。我们的研究利用在小鼠模型中检测生长因子BDNF的新技术进步，将使我们能够确定在儿童和青少年时期的脆弱时期提供的SSRI如何影响对这一关键生长因子的调节，以调节结构和功能的神经可塑性，导致在关键的儿童脆弱时期对SSRI的长期异常行为反应。

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.