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.
Uhlmann
Erik J
EJ
Department of Neurology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA. gutmannd@heuro.wustl.edu
Wong
Michael
M
Baldwin
Rebecca L
RL
Bajenaru
M Livia
ML
Onda
Hiroaki
H
Kwiatkowski
David J
DJ
Yamada
Kelvin
K
Gutmann
David H
DH
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