TY - JOUR
T1 - Microglial activation during epileptogenesis in a mouse model of tuberous sclerosis complex
AU - Zhang, Bo
AU - Zou, Jia
AU - Han, Lirong
AU - Rensing, Nicholas
AU - Wong, Michael
N1 - Publisher Copyright:
Wiley Periodicals, Inc. © 2016 International League Against Epilepsy
PY - 2016
Y1 - 2016
N2 - Objective: 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 (Tsc1GFAPCKO mice), and to test the hypothesis that microglial activation contributes to epileptogenesis in this mouse model. Methods: Microglial and astrocyte activation was examined in Tsc1GFAPCKO 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. Results: Microglial cell number and size were increased in cortex and hippocampus of 3- to 4-week-old Tsc1GFAPCKO mice, which correlated with the onset of seizures. Minocycline treatment prevented the increase in number and cell size of microglia in 4-week-old Tsc1GFAPCKO mice. However, minocycline treatment had no effect on astrocyte proliferation and cytokine/chemokine expression and the progression of seizures in Tsc1GFAPCKO mice. Significance: Microglia cell number and size are abnormal in Tsc1GFAPCKO 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.
AB - Objective: 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 (Tsc1GFAPCKO mice), and to test the hypothesis that microglial activation contributes to epileptogenesis in this mouse model. Methods: Microglial and astrocyte activation was examined in Tsc1GFAPCKO 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. Results: Microglial cell number and size were increased in cortex and hippocampus of 3- to 4-week-old Tsc1GFAPCKO mice, which correlated with the onset of seizures. Minocycline treatment prevented the increase in number and cell size of microglia in 4-week-old Tsc1GFAPCKO mice. However, minocycline treatment had no effect on astrocyte proliferation and cytokine/chemokine expression and the progression of seizures in Tsc1GFAPCKO mice. Significance: Microglia cell number and size are abnormal in Tsc1GFAPCKO 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.
KW - Astrocyte
KW - Epilepsy
KW - Inflammation
KW - Microglia
KW - Seizure
UR - http://www.scopus.com/inward/record.url?scp=84984985170&partnerID=8YFLogxK
U2 - 10.1111/epi.13429
DO - 10.1111/epi.13429
M3 - Article
C2 - 27263494
AN - SCOPUS:84984985170
SN - 0013-9580
VL - 57
SP - 1317
EP - 1325
JO - Epilepsia
JF - Epilepsia
IS - 8
ER -