Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures.
Persons affected with tuberous sclerosis complex (TSC) develop a wide range of neurological abnormalities including aberrant neuronal migration and seizures. In an effort to model TSC-associated central nervous system abnormalities in mice, we generated two independent lines of astrocyte-specific Tsc1 conditional knockout mice by using the Cre-LoxP system. Astrocyte-specific Tsc1-null mice exhibit electroencephalographically proven seizures after the first month of age and begin to die at 3 to 4 months. Tsc1-null mice show significant increases in astrocyte numbers throughout the brain by 3 weeks of age and abnormal neuronal organization in the hippocampus between 3 and 5 weeks. Moreover, cultured Tsc1-null astrocytes behave similar to wild-type astrocytes during log phase growth but demonstrate increased saturation density associated with reduced p27(Kip1) expression. Collectively, our results demonstrate that astrocyte-specific disruption of Tsc1 in mice provides a context-dependent growth advantage for astrocytes that results in abnormalities in neuronal organization and epilepsy.
Department of Neurology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA. gutmannd@heuro.wustl.edu
Erik J
EJ
Uhlmann
Michael
M
Wong
Rebecca L
RL
Baldwin
M Livia
ML
Bajenaru
Hiroaki
H
Onda
David J
DJ
Kwiatkowski
Kelvin
K
Yamada
David H
DH
Gutmann
D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics; D002455:Cell Division; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics / Q000473:pathology*; D005911:Gliosis / Q000473:pathology; D006624:Hippocampus / Q000002:abnormalities* / Q000473:pathology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology*; D011506:Proteins / Q000032:analysis / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D011506:Proteins; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27