Enhancing synaptic and structural plasticity by manipulating PirB

描述(申请人提供)：当大脑发育时，它使用特定的规则来确定两个神经元是否应该在它们之间形成突触。例如，“一起发射”的神经元经常会“连线在一起”，而那些“不同步、失去联系”的神经元则会失去联系。这些突触可塑性规则对于确定大脑皮质的哪一部分以及哪些细胞将专门用于某些过程非常重要，比如双眼视觉。沙茨实验室发现，PirB(配对免疫球蛋白样受体B)是一种免疫受体，通常存在于神经元中，与人类同源，它对小鼠视觉皮质的可塑性起到了刹车的作用。从基因上去除老鼠体内的PirB(即“去除刹车”)可以增强视觉皮质的可塑性。成年人大脑皮质可塑性的“刹车”在从损伤(如中风)、神经退行性疾病(如阿尔茨海默氏症)或发育障碍(如自闭症或弱视)中恢复时可能很重要。因此，该实验室的首要任务之一是了解通过从小鼠身上移除PirB基因或当PirB基因被直接阻断而增强可塑性的细胞和分子机制。这个项目的第一个目标是了解PirB是否对导致成年期可塑性降低的突触可塑性规则(如一起开火，一起电线)产生影响。这将通过使用皮质切片电生理学比较正常大脑和缺乏PirB的大脑来完成。这个项目的第二个目标是直接阻断PirB的功能，看看这些和其他可塑性规则是否可以立即改变。这将使用皮质切片电生理学和活的双光子激发显微镜来观察。如果细胞确实改变了它们的结构和突触可塑性规则，那么通过阻断PirB来剧烈地“拆除刹车”可能会提供新的方法来克服大脑的损伤、疾病或发育障碍。

DESCRIPTION (provided by applicant): When the brain is developing, it uses specific rules to determine if two neurons should form a synapse between them or not. For example, neurons that "fire together" will often "wire together", and those that are "out of synch, lose their link" These synaptic plasticity rules are very important in determining what portion of the cortex and which cells will be devoted to certain processes, such as binocular vision. The Shatz laboratory has found that PirB (paired immunoglobulin-like receptor B), an immune receptor found normally in neurons and having a human ortholog, acts as a "brake" on plasticity in the mouse visual cortex. Removing PirB genetically in the mouse (i.e. "removing the brake") enhances plasticity in visual cortex. "Removing the brake" on cortical plasticity in the adult could be important in recovering from injury (e.g. stroke), neurodegenerative disease (e.g. Alzheimer's), or developmental disorders (e.g. autism or amblyopia). Therefore, one of the greatest priorities of the lab is to understand the cellular and molecular mechanisms that underlie the enhanced plasticity that comes from removing PirB genetically from the mouse, or when PirB is directly blocked. The first goal of this project is to understand if PirB has an effect on synaptic plasticiy rules (such as the rule "fire together, wire together") that cause plasticity to decrease in adulthood. This will be done by comparing normal brains and brains lacking PirB using cortical slice electrophysiology. The second goal of this project is to directly block the function of PirB and see if these and other plasticity rules can be changed immediately. This will be observed using cortical slice electrophysiology and live two-photon excitation microscopy. If cells do modify their structure and synaptic plasticity rules, then acutely "removing the brake" by blocking PirB could provide new ways to overcome injury, disease, or developmental disorders of the brain.