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.

Public Health Relevance

Understanding cellular mechanisms governing brain developmental processes is vital and may inform approaches to treat neurodevelopmental pathologies. This proposal pioneers a novel approach to understand microglial cell activities and test the involvement of one of its major receptors in developmental brain function and in a developmental epileptic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Career Transition Award (K22)
Project #
4K22NS104392-03
Application #
9755047
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Leenders, Miriam
Project Start
2017-12-08
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Virginia
Department
Neurosciences
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Bosco, Dale B; Zheng, Jiaying; Xu, Zhiyan et al. (2018) RNAseq analysis of hippocampal microglia after kainic acid-induced seizures. Mol Brain 11:34
Eyo, Ukpong B; Mo, Mingshu; Yi, Min-Hee et al. (2018) P2Y12R-Dependent Translocation Mechanisms Gate the Changing Microglial Landscape. Cell Rep 23:959-966
Zhao, Xiaoliang; Eyo, Ukpong B; Murugan, Madhuvika et al. (2018) Microglial interactions with the neurovascular system in physiology and pathology. Dev Neurobiol 78:604-617
Eyo, Ukpong B; Bispo, Ashley; Liu, Junting et al. (2018) The GluN2A Subunit Regulates Neuronal NMDA receptor-Induced Microglia-Neuron Physical Interactions. Sci Rep 8:828