Bacterial influences on synapse formation

描述（由申请人提供）：遗传和环境因素在影响和可能导致神经发育障碍（如自闭症、精神发育迟滞和精神分裂症）方面起着重要作用。遗传分析的最新进展揭示了许多与这些疾病的家族形式有关的基因。然而，人们对环境如何导致这些疾病或环境如何与已确定的遗传原因相互作用知之甚少。我们提出，在发育过程中肠道微生物的异常定植导致参与大脑发育的基因的异常表达水平，特别是在突触形成中。我们假设肠道微生物的不正确定植可能通过促进异常突触形成而加剧或驱动行为缺陷，导致神经元回路和功能改变。我们建议研究斑马鱼发育过程中早期肠道微生物群定植和突触细胞粘附分子（如神经配素）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，神经元活动和行为的发展的后果，因为我们可以操纵宿主遗传学和微生物群落，并在真实的时间内在活的青少年和成年人中跟踪定义的神经元群体的发展。我们还建议确定是否存在一个关键时期，在此期间，其成员表达特定性状的微生物群的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，我们将直接测试一种生态失调的促炎微生物群是否可以改变年轻和成年动物的突触发育、神经元回路的形成、神经元活动和行为。我们提出的实验将首次全面了解微生物信号如何影响神经元解剖学和生理学的发育，以及这如何影响发育后期和成年人的行为。揭示和表征微生物群与驱动突触形成的基因之间的相互作用将对目前诊断患有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.