Enhancing synaptic and structural plasticity by manipulating PirB

描述（由申请人提供）：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”的神经元通常会“连接在一起”，而那些“不同步，失去联系”的神经元这些突触可塑性规则在确定皮层的哪个部分以及哪些细胞将致力于某些过程（如双眼视觉）方面非常重要。Shatz实验室发现，PirB（成对免疫球蛋白样受体B）是一种通常在神经元中发现的免疫受体，具有人类直系同源物，在小鼠视觉皮层中充当可塑性的“刹车”。在小鼠中遗传地去除PirB（即“去除制动器”）增强视觉皮层的可塑性。在成年人中，“移除大脑皮层可塑性的制动器”对于从损伤（例如中风）、神经退行性疾病（例如阿尔茨海默氏症）或发育障碍（例如自闭症或弱视）中恢复可能是重要的。因此，该实验室的最大优先事项之一是了解增强可塑性的细胞和分子机制，这些机制来自于从小鼠中去除PirB基因，或者当PirB被直接阻断时。该项目的第一个目标是了解PirB是否对突触可塑性规则（例如规则“一起发射，一起连接”）产生影响，这些规则导致成年后可塑性下降。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止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体双光子激发显微镜观察。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来急性“移除刹车”可以提供克服大脑损伤，疾病或发育障碍的新方法。

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.