Antipsychotic drug and cortical development

描述（由申请人提供）：尽管对孩子有未知的长期风险，但许多孕妇必须服用抗精神病药物（APD），因为药物治疗的中断会危及妇女进行日常生活和照顾孩子的能力。APD调节多巴胺能和/或多巴胺能突触传递。血清素和多巴胺还调节树突发育，而树突发育又是神经元连接和功能的关键决定因素。因此，在发育过程中，有限的APD暴露时间可能会导致皮质电路的长期，行为上显着的变化。我们的初步数据支持这一假设。APD处理的小鼠似乎在评估几个皮层区域功能的行为测试中受损。在这些区域中，皮质锥体细胞树突通常通过建设性和退行性事件的组合来发育，并且早期APD暴露可以加速、延迟或抑制这些事件。目的1研究正常个体发育过程中树突状形态的变化。目的2研究APD对树突结构的长期影响以及APD对树突形态个体发育的影响。目的3研究APD早期暴露对行为和认知的长期影响，并探讨行为训练对APD诱导的树突状形态改变的潜在正常化影响。在目标4中，通过无效突变和测量实验治疗对应激反应的影响来消融单个单胺受体，以研究APD诱导效应的一些潜在机制。我们的研究结果有助于评估孕妇使用APD的潜在长期风险。我们的方法可用于评估母亲使用其他治疗药物和非法药物的风险，并可用于研究各种神经发育障碍的生物学。因此，我们的研究结果可以帮助设计新的治疗方法，改善临床结果。

DESCRIPTION (provided by applicant): Despite unknown, long-term risks for their children, many pregnant women must take antipsychotic drugs (APDs) because interruption of pharmacotherapy would jeopardize the women's ability to carry on their daily lives and to care for their children. APDs modulate serotonergic and/or dopaminergic synaptic transmission. Serotonin and dopamine also regulate dendritic development which, in turn, is a key determinant of neuronal connectivity and function. Thus, limited periods of APD exposure during development may cause long-lasting, behaviorally significant changes in cortical circuitry. Our preliminary data support this hypothesis. APD-treated mice appear to be impaired in behavioral tests that assess the function of several cortical areas. In these areas, cortical pyramidal cell dendrites normally develop by a combination of constructive and regressive events and early APD exposure can accelerate, retard or inhibit these events. Aim 1 investigates the normal ontogenetic progression of changes in dendritic form. Aim 2 examines the long-term effects of APDs on dendritic architecture and effects of APDs on the ontogeny of dendritic form. Aim 3 investigates the long-term effects of early APD exposure on behavior and cognition, and also examines potential normalizing influences of behavioral training on APD-induced alterations of dendritic form. In Aim 4, ablation of individual monoamine receptors by null mutations and measurements of the effects of experimental treatments on stress responses are used to investigate some potential mechanisms of APD-induced effects. Our results help assess the potential long-term risks of APD use by pregnant women. Our method can be applied to assess the risks of maternal use of other therapeutic- and illegal drugs, and can be used to study the biology of various neurodevelopmental disorders. Thus, our results can aid in the design of new therapies that improve clinical outcomes.