Our initial grant funding focused on the earliest period following experimentally-induced seizures. We documented robust physical interactions between microglia and neurons in epileptic contexts and concluded that microglia provide beneficial functions in the acute seizures. In this renewal, we will further investigate microglial activities in the epileptic brain in vivo and combine cellular and functional imaging with electrophysiological and behavioral studies in experimental mouse seizure models. We will extend our findings from the initial funding cycle to further characterize microglial activities in the epileptic brain following seizures and provide further evidence of microglial neuroprotection in the acute phase of kainic acid (KA)-induced seizures. In addition, we will investigate microglial roles in the epileptic brain in the chronic phase of epilepsy using microglial ablation and chemogenetic DREADD approaches. Our central hypothesis is that microglia play opposing roles during the acute phase of seizures and the chronic phase of epileptogenesis. This hypothesis will be tested along the following specific aims:
In Aim 1, we will investigate the dynamics and function of seizure-induced microglial process pouches.
In Aim 2, we will determine microglial contributions to epileptogenesis. Finally, in Aim 3, we will ascertain opposing microglial roles in acute seizures and chronic epilepsy using DREADD approaches. When completed, this grant will extend the findings of the initial funding to elucidate the beneficial roles for microglia in the acute phase of seizures Furthermore, this renewal will highlight detrimental contributions by microglia in promoting seizure-induced neurogenesis, neuronal sprouting, neuronal excitability and spontaneous seizures in the chronic phase of seizures. This study will not only improve our understanding of microglial mechanism to epileptogenesis but also demonstrate that microglia are potential therapeutic targets for the treatment seizures and epilepsy.

Public Health Relevance

The current proposal aims to study the role of microglia in epilepsy, with particular focus on testing the differential function of microglia in acute seizure and chronic epilepsy. This study will not only improve our understanding of microglial mechanism to epileptogenesis but also demonstrate that microglia are potential therapeutic targets for the treatment seizures and epilepsy. This mechanism may serve as a common model to address the role of microglia in the pathogenesis of other neurological and neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS088627-09
Application #
10145803
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Leenders, Miriam
Project Start
2014-05-01
Project End
2024-02-29
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
9
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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
Qin, Chuan; Liu, Qian; Hu, Zi-Wei et al. (2018) Microglial TLR4-dependent autophagy induces ischemic white matter damage via STAT1/6 pathway. Theranostics 8:5434-5451
Beier, Eric E; Neal, Matthew; Alam, Gelerah et al. (2017) Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide. Neurobiol Dis 108:115-127
Eyo, Ukpong B; Murugan, Madhuvika; Wu, Long-Jun (2017) Microglia-Neuron Communication in Epilepsy. Glia 65:5-18
Tian, Dai-Shi; Peng, Jiyun; Murugan, Madhuvika et al. (2017) Chemokine CCL2-CCR2 Signaling Induces Neuronal Cell Death via STAT3 Activation and IL-1? Production after Status Epilepticus. J Neurosci 37:7878-7892
Qin, Chuan; Fan, Wen-Hui; Liu, Qian et al. (2017) Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3 Pathway. Stroke 48:3336-3346
Liu, Yong; Zhou, Li-Jun; Wang, Jun et al. (2017) TNF-? Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury. J Neurosci 37:871-881
Peng, Jiyun; Gu, Nan; Zhou, Lijun et al. (2016) Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury. Nat Commun 7:12029

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