Epilepsy represents a neurological disorder that can manifest in uncontrolled seizures in patients. Microglia are exquisitely sensitive to disruptions i the central nervous system. Since epilepsy is characterized by neuronal hyperactivity activity rooted in excessive glutamate release and ionic imbalance, it is conceivable that microglia may perform functions to reduce neuronal dysfunction and promote neuronal health during the pathology. In our preliminary studies, we have found that microglia respond by robust process extension making increasing contact with neurons during elevated glutamate levels in acute brain slices. Moreover, in three different models of epileptiform activity, microglial processes focus on neuronal dendrites and microglial ablation reduces behavioral seizure scores. Based on our preliminary results, we hypothesize that during increased glutamate levels hyperactive neurons signal to microglia inducing their process extension. Additionally, during hyperactive neuronal activity, microglial processes focus on neuronal elements with a consequence to downregulate such hyperactivity which is critical in limiting behavioral seizure outcome and promoting neuronal survival. We will now test this hypothesis along with the following specific aims.
In Aim 1, we will determine the underlying mechanisms behind glutamate-induced microglial process extension elucidating the neuronal receptors initiating and the released chemoattractants mediating the process extension signal.
In Aim 2, we will determine the targets of microglial process focus as well as the chemoattractants mediating the response in three models of epileptiform activity in acute brain slices.
In Aim 3, we will extend our observations in acute brain slices to in vivo live brain and determine the role of microglia in epilepsy-induced seizure behaviors and neuronal cell death by microglial ablation and genetic deletion of the unique microglial P2Y12 receptor. These studies are the first to investigate the microglial dynamics during acute epilepsy. They will increase our understanding of the mechanisms underlying microglial-neuronal interactions during epileptic activity and the neuroprotective potential of microglia in epilepsy. In addition, the outcome of these studies will provide new data that could inform the development of novel therapies in the treatment of epileptic disorders.

Public Health Relevance

The current proposal aims to determine the activities and function of microglia during hyperactive neuronal activity as occurs during epilepsy. Specifically, the experiments outlined in the proposal will enhance our understanding of the mechanisms underlying microglial-neuronal interactions during epileptic activity and the neuroprotective potential of microglia during epilepsy. The outcome of these studies may potentially inform new strategies in the development of therapy against epileptic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS088627-01
Application #
8764941
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Whittemore, Vicky R
Project Start
2014-05-01
Project End
2019-02-28
Budget Start
2014-05-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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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
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
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
Eyo, Ukpong B; Murugan, Madhuvika; Wu, Long-Jun (2017) Microglia-Neuron Communication in Epilepsy. Glia 65:5-18
Gu, Nan; Eyo, Ukpong B; Murugan, Madhuvika et al. (2016) Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain. Brain Behav Immun 55:82-92
Swiatkowski, P; Murugan, M; Eyo, U B et al. (2016) Activation of microglial P2Y12 receptor is required for outward potassium currents in response to neuronal injury. Neuroscience 318:22-33
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
Eyo, Ukpong B; Peng, Jiyun; Murugan, Madhuvika et al. (2016) Regulation of Physical Microglia-Neuron Interactions by Fractalkine Signaling after Status Epilepticus. eNeuro 3:
Gu, Nan; Peng, Jiyun; Murugan, Madhuvika et al. (2016) Spinal Microgliosis Due to Resident Microglial Proliferation Is Required for Pain Hypersensitivity after Peripheral Nerve Injury. Cell Rep 16:605-14

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