Microglial P2Y12 Receptors in Normal Developmental Physiology and Seizures

本次K22奖拟议研究的总体目标是检验以下假设： P2 Y12受体在正常发育过程中调节原代小胶质细胞功能， 有助于生理神经元的兴奋性，并因此从一个 发育性癫痫在第一阶段，我将发展以下方面的技术技能：（i） 分辨率双光子在体成像技术和（ii）脑电图（EEG） 发育中小鼠的植入性癫痫发作测量。在开发了这些技术之后， 在独立的第二阶段，我将讨论这一建议的具体目标，包括确定 P2 Y12受体在发育脑中小胶质细胞定植和吞噬作用中的作用 (Aim 1）确定小胶质细胞P2 Y12受体在突触结构和功能中的作用 (Aim 2）;以及确定小胶质细胞P2 Y12受体在癫痫发作中的任何贡献 Dravet综合征发育性癫痫发作模型的表型和结局。当 完成后，该提案将提供P2 Y12受体在小胶质细胞中的作用的理解。 活动及其对神经元成熟和癫痫发作表型的影响， 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.