Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus

• Published in: Glia Vol. 67; no. 8; pp. 1434 - 1448
• Main Authors: Feng, Lijie, Murugan, Madhuvika, Bosco, Dale B., Liu, Yong, Peng, Jiyun, Worrell, Gregory A., Wang, Hai‐Long, Ta, Lauren E., Richardson, Jason R., Shen, Yuxian, Wu, Long‐Jun
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.08.2019; Wiley Subscription Services, Inc
• Subjects: Animals; Attenuation; Brain; Calcium-Binding Proteins - metabolism; CC chemokine receptors; CCR2 protein; Cell activation; Cell Death; Cell Proliferation; Cerebrospinal fluid; colony stimulating factor 1 receptor; Convulsions & seizures; CX3C Chemokine Receptor 1 - genetics; CX3C Chemokine Receptor 1 - metabolism; CX3CR1 protein; Disease Models, Animal; Epilepsy; Gliosis - etiology; Gliosis - physiopathology; Hippocampus; Hippocampus - physiopathology; Infiltration; Kainic Acid; Male; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins - metabolism; Microglia; Microglia - physiology; Monocyte chemoattractant protein 1; Monocytes; Monocytes - physiology; Neuroimaging; Neurons - physiology; Neuroprotection; Pharmacology; Physical characteristics; proliferation; Receptor, Macrophage Colony-Stimulating Factor - metabolism; Receptors, CCR2 - genetics; Receptors, CCR2 - metabolism; Recording; Seizures; Status Epilepticus - complications; Status Epilepticus - physiopathology; Therapeutic applications; Tissue Culture Techniques; epilepsy; monocytes; colony stimulating factor 1 receptor; proliferation; microglia; infiltration
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23616

Microglial activation has been recognized as a major contributor to inflammation of the epileptic brain. Seizures are commonly accompanied by remarkable microgliosis and loss of neurons. In this study, we utilize the CX3CR1GFP/+ CCR2RFP/+ genetic mouse model, in which CX3CR1+ resident microglia and CCR2+ monocytes are labeled with GFP and RFP, respectively. Using a combination of time‐lapse two‐photon imaging and whole‐cell patch clamp recording, we determined the distinct morphological, dynamic, and electrophysiological characteristics of infiltrated monocytes and resident microglia, and the evolution of their behavior at different time points following kainic acid‐induced seizures. Seizure activated microglia presented enlarged somas with less ramified processes, whereas, infiltrated monocytes were smaller, highly motile cells that lacked processes. Moreover, resident microglia, but not infiltrated monocytes, proliferate locally in the hippocampus after seizure. Microglial proliferation was dependent on the colony‐stimulating factor 1 receptor (CSF‐1R) pathway. Pharmacological inhibition of CSF‐1R reduced seizure‐induced microglial proliferation, which correlated with attenuation of neuronal death without altering acute seizure behaviors. Taken together, we demonstrated that proliferation of activated resident microglia contributes to neuronal death in the hippocampus via CSF‐1R after status epilepticus, providing potential therapeutic targets for neuroprotection in epilepsy. Main Points Microglia and monocytes contribute to observed hippocampal microgliosis after seizures. Microglia, but not monocytes, proliferate in the hippocampus after seizures. Inhibiting microglial proliferation does not affect seizure severity but attenuated seizure induced neuronal loss.