Microglial activation during epileptogenesis in a mouse model of tuberous sclerosis complex.
Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by tumor formation in multiple organs and severe neurologic manifestations, including epilepsy, intellectual disability, and autism. Abnormalities of both neurons and astrocytes have been implicated in contributing to the neurologic phenotype of TSC, but the role of microglia in TSC has not been investigated. The objectives of this study were to characterize microglial activation in a mouse model of TSC, involving conditional inactivation of the Tsc1 gene predominantly in glial cells (Tsc1(GFAP) CKO mice), and to test the hypothesis that microglial activation contributes to epileptogenesis in this mouse model.



Microglial and astrocyte activation was examined in Tsc1(GFAP) CKO mice by ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein immunohistochemistry. Cytokine and chemokine expression was evaluated with quantitative polymerase chain reaction. Seizures were monitored by video-electroencephalography (EEG). The effect of minocycline in inhibiting microglial and astrocyte activation, cytokine expression, and seizures was tested.



Microglial cell number and size were increased in cortex and hippocampus of 3- to 4-week-old Tsc1(GFAP) CKO mice, which correlated with the onset of seizures. Minocycline treatment prevented the increase in number and cell size of microglia in 4-week-old Tsc1(GFAP) CKO mice. However, minocycline treatment had no effect on astrocyte proliferation and cytokine/chemokine expression and the progression of seizures in Tsc1(GFAP) CKO mice.



Microglia cell number and size are abnormal in Tsc1(GFAP) CKO mice, and minocycline treatment inhibits this microglia activation, but does not suppress seizures. Microglia may play a role in the neurologic manifestations of TSC, but additional studies are needed in other models and human studies to determine whether microglia are critical for epileptogenesis in TSC.
Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
Bo
B
Zhang
Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
Jia
J
Zou
Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
Lirong
L
Han
Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
Nicholas
N
Rensing
Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
Michael
M
Wong
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000209:etiology* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014402:Tuberous Sclerosis / Q000150:complications* / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D014741:Video Recording
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D012333:RNA, Messenger; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D008911:Minocycline
Astrocyte; Epilepsy; Inflammation; Microglia; Seizure