ANTIPSYCHOTIC DRUGS 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继续日常生活和照顾孩子的能力。apd调节血清素和/或多巴胺能突触传递。5 -羟色胺和多巴胺也调节树突的发育，这反过来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，APD暴露的有限时间可能会导致长期的、行为上显著的皮质回路变化。我们的初步数据支持这一假设。在评估几个皮质区域功能的行为测试中，apd治疗的小鼠似乎受到损害。在这些区域，皮层锥体细胞树突通常通过建设性和退行性事件的结合而发育，早期APD暴露可加速、延缓或抑制这些事件。目的1研究树突形态变化的正常个体发育过程。目的2研究apd对树突结构的长期影响以及apd对树突形态个体发生的影响。目的3研究早期APD暴露对行为和认知的长期影响，并研究行为训练对APD诱导的树突形态改变的潜在正常化影响。在Aim 4中，通过零突变消融单个单胺受体和测量实验处理对应激反应的影响来研究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性和非法药物的风险，并可用于研究各种神经发育障碍的生物学。因此，我们的结果可以帮助设计改善临床结果的新疗法。

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.