Activity-Dependent Regulation of Early Stages in Synapse Formation

突触形成早期阶段的活动依赖性调节神经系统的功能依赖于适当的连接，即突触的建立。这个项目的假设是突触形成的早期事件是由电活动决定的。电活动的改变会改变神经递质表达，遵循稳态模式（Borodinsky等人，2004）。这一发现引发了一个问题，即神经递质表达的改变是否会导致脊髓轴突的改变。不同神经元类型的轴突寻径模式将在活动受到干扰后被遵循。实验还将解决神经活动影响突触后细胞中表达的神经递质受体类别的假设。该项目的最终目标是验证这样一个假设，即当活动被操纵时，神经元和靶细胞之间可以形成新的突触，即不同递质的表达将与相应受体的表达相匹配。拟议中的项目对发育神经科学领域很重要，因为它挑战了神经系统发育的早期事件完全由预定的遗传程序控制，独立于电活动的观点。在这项研究中获得的信息可能对我们如何看待神经系统发育布线障碍和相关病理具有重要意义。调节目标细胞中分泌特定递质的神经元数量和递质敏感性的能力具有巨大的社会效益，为神经系统疾病提供了潜在的治疗方法。美国国家科学基金会对目前提案的支持对于作为一名独立科学家或一个代表性不足的群体的成员的进步至关重要。这笔拨款将用于继续培训学生，并将允许首席研究员发展作为主管的技能。NSF的支持将确保结果在科学期刊上发表，并参与科学会议以传播该提案的结果并加强对神经系统发育的理解。

Laura N. Borodinsky Proposal # 0516871Activity-dependent regulation of early stages in synapse formationNervous system function relies on the establishment of appropriate connections, called synapses. The hypothesis of the proposed project is that early events in synapse formation are shaped by electrical activity. Alterations in electrical activity modify neurotransmitter expression following a homeostatic paradigm (Borodinsky et al., 2004). This finding leads to the question whether altered neurotransmitter expression causes rerouting of axons in the spinal cord. Axonal pathfinding patterns for different neuronal types will be followed after activity has been perturbed. The experiments will also address the hypothesis that neural activity influences the classes of neurotransmitter receptors expressed in postsynaptic cells. The ultimate goal of the project will be to test the hypothesis that novel synapses between neurons and target cells can be formed when activity is manipulated, i.e. that expression of different transmitters will be matched by the expression of corresponding receptors. The proposed project is important for the field of developmental neuroscience because it challenges the view that early events in nervous system development are governed entirely by a predetermined genetic program, independent of electrical activity.The information gained in this study could have significant implications for how we think about disorders in developmental wiring of the nervous system and related pathologies. The ability to regulate the number of neurons secreting particular transmitters and transmitter sensitivity in target cells has the power to be of substantial societal benefit, providing potential therapies for neurological disorders.Support from NSF for the present proposal will be crucial in the advancement as an independent scientist of a member of an underrepresented group. This grant will allow continued training of students, and will allow the principal investigator to develop skills as a supervisor. NSF support will ensure publication of results in scientific journals, and participation in scientific meetings to disseminate the results from this proposal and enhance understanding of nervous system development.