Tools for manipulating protein condensates at the synapse

不同的神经功能是由浓缩的生物分子集合驱动的，这种集合被称为凝聚体。为 例如，突触后密度，一种锚定神经递质受体和信号分子的结构 在突触，被认为是通过相分离过程形成凝析油，涉及多个高度- 网络支架分子。突触后凝集物的生物物理和材料性质是如何 对突触功能和可塑性有贡献吗？该项目将开发和扩展方法，允许诱导 生物分子凝聚体的形成和/或破坏，将它们应用于神经元以调节物质 突触后密度的特性，同时评估突触的结构和功能。目标1 将开发和应用工具来快速增加突触后密度的刚性并评估功能性 对突触结构和可塑性的影响。目标2将重点放在诱导增加流动性的方法上 突触后密度，降低凝集液中涉及的特定支架分子的价态 队形。这项工作将开发通用工具，在整个过程中操纵生物分子凝析油 神经系统，与神经元发育、神经精神疾病、成瘾等有关 大脑紊乱。

Diverse neural functions are driven by concentrated biomolecular assemblies known as condensates. For example, the postsynaptic density, a structure that anchors neurotransmitter receptors and signaling molecules at the synapse, is thought to form a condensate through a phase-separation process involving multiple highly- networked scaffold molecules. How do the biophysical and material properties of the postsynaptic condensate contribute to synaptic function and plasticity? This project will develop and extend methods that allow inducible formation and/or disruption of biomolecular condensates, applying them in neurons to modulate the material properties of the postsynaptic density while simultaneously assessing synapse structure and function. Aim 1 will develop and apply tools to rapidly increase the rigidity of the postsynaptic density and assess the functional consequences on synaptic structure and plasticity. Aim 2 will focus on methods to inducibly increase the fluidity of the postsynaptic density, reducing the valency of specific scaffold molecules involved in condensate formation. This work will develop general-use tools for manipulating biomolecular condensates throughout the nervous system, with implications for neuronal development, neuropsychiatric diseases, addiction and other brain disorders.