Microglial P2Y12 Receptors in Normal Developmental Physiology and Seizures

这项K22奖项的拟议研究的总体目标是检验以下假设 P2Y12受体在正常发育和发育过程中调节初级小胶质细胞功能 有助于生理性神经元兴奋性，从而导致 发育性癫痫。在指导阶段I，我将发展(I)高的技术技能 分辨率双光子活体成像技术和(Ii)脑电信号 发育期小鼠的植入惊厥测量。开发了这些技术后，在 独立的第二阶段，我将阐述这项提案的具体目标，包括确定 P2Y12受体在发育中脑内小胶质细胞定植和吞噬中的作用 (目标1)：确定小胶质细胞P2Y12受体在突触结构和功能中的作用 (目标2)；以及确定小胶质细胞P2Y12受体在癫痫发作中的作用 德拉韦综合征发育性癫痫模型的表型和结局。什么时候 完成后，该提案将提供对P2Y12受体在小胶质细胞中作用的理解 活动及其对神经元成熟和癫痫表型的影响 为未来的治疗方法提供信息。

The overall goal of the proposed research for this K22 award is to test the hypothesis that P2Y12 receptors regulate prime microglial cell function during normal development and contribute to physiological neuronal excitability and consequently outcomes from a developmental seizure disorder. In the mentored Phase I, I will develop technical skill in (i) high resolution two photon in vivo imaging techniques in and (ii) electroencephalogram (EEG) implantation seizure measurement in developing mice. Having developed these techniques, in the independent Phase II, I will address the specific aims of this proposal including determining the role of P2Y12 receptors in microglial colonization and phagocytosis in the developing brain (Aim 1); determining the role of microglial P2Y12 receptors in synaptic structure and function (Aim 2); and determining any contributions of microglial P2Y12 receptors in the seizure phenotypes and outcomes in a developmental seizure model of Dravet Syndrome. When completed, this proposal will provide an understanding of P2Y12 receptor roles in microglial activities and its consequences on neuronal maturation and seizure phenotypes that could inform future therapeutic approaches.