Bacterial influences on synapse formation

描述（由申请人提供）：遗传和环境因素都在影响和可能导致神经发育障碍，如自闭症，智力迟钝和精神分裂症方面发挥重要作用。遗传分析的最新进展揭示了一些与这些疾病的家族形式有关的基因。然而，对于环境如何导致这些疾病，或者环境如何与已确定的遗传原因相互作用，我们知之甚少。我们认为，发育过程中肠道的异常微生物定植导致参与大脑发育的基因表达水平异常，特别是突触形成。我们假设不正确的肠道微生物定植可能通过促进异常突触形成而导致神经回路和功能改变，从而加剧或驱动行为缺陷。我们建议研究斑马鱼发育过程中早期肠道微生物群定植与突触细胞粘附分子（如神经素）表达之间的相互作用。该模型提供了一个无与伦比的机会来研究改变肠道微生物定植对突触形成、神经元回路发育、神经元活动和行为的影响，因为我们可以操纵宿主遗传和微生物群落，并实时跟踪活的幼虫和成年虫中定义的神经元种群的发育。我们还建议确定是否存在一个关键时期，在此期间，其成员表达特定特征的微生物群定植是正常突触发育所必需的，并了解微生物群如何向发育中的大脑发出信号，以促进正常行为所需的正常突触形成。最后，我们将直接测试益生菌、促炎菌群是否能改变突触发育、神经元回路的形成、神经元活动和行为，在幼龄和成年动物中都是如此。我们提出的实验将提供微生物信号如何影响神经元解剖和生理发育的第一个综合观点，以及这如何影响发育后期和成人的行为。揭示和描述微生物群和驱动突触形成的基因之间的相互作用将对目前诊断为神经发育障碍的个体的治疗方法产生巨大影响。

DESCRIPTION (provided by applicant): Both genetic and environmental factors play significant roles in influencing and perhaps causing neurodevelopmental disorders such as autism, mental retardation, and schizophrenia. Recent advances in genetic analysis have revealed a number of genes linked to familial forms of these disorders. Very little is known, however, about how the environment may contribute to these disorders, or how the environment may interact with identified genetic causes. We propose that abnormal microbial colonization of the gut during development leads to aberrant expression levels of genes that are involved in brain development, specifically in synapse formation. We hypothesize that incorrect microbial colonization of the gut may exacerbate or drive behavioral deficits by promoting aberrant synapse formation that results in altered neuronal circuitry and function. We propose to examine interactions between early gut colonization by the microbiota and expression of synaptic cell adhesion molecules, such as Neuroligins, during development in zebrafish. This model provides an unparalleled opportunity to study the consequences of altered gut microbial colonization on synapse formation, development of neuronal circuitry, neuronal activity, and behavior, because we can manipulate both host genetics and microbial communities and follow development of defined neuronal populations in real time in living juveniles and adults. We also propose to determine whether there is a critical period during which colonization by a microbiota whose members express specific traits is required for normal synapse development, and to learn how the microbiota signals to the developing brain to promote the normal synapse formation required for normal behavior. Finally, we will test directly whether a dysbiotic, pro-inflammatory microbiota can alter synapse development, formation of neuronal circuitry, neuronal activity, and behavior, in both young and adult animals. Our proposed experiments will provide the first comprehensive view of how microbial signals affect development of neuronal anatomy and physiology and how this affects behavior at later stages of development and in adults. Revealing and characterizing an interaction between the microbiota and the genes that drive synapse formation would have a dramatic impact on current treatment approaches for individuals diagnosed with neurodevelopmental disorders.