All Phenotypes Tg(Gfap-cre)1Sbk MGI Mouse

premature death ( J:75500 , J:149829 )

• all die by 29 weeks of age, with an average of 10 weeks (J:75500)

seizures ( J:75500 )

• 11 of 25 develop seizures by 9 weeks of age; symptoms include episodes of front-paw tremors followed by spasms of hind legs

tonic-clonic seizures ( J:149829 )

• beyond 6 weeks, mice exhibit epileptiform activity associated with tonic-clonic seizures

• mice exhibit subclinical electrographic seizures lasting for at least 10 seconds largely without obvious behavioral changes unlike in wild-type mice

• at 6 weeks, two of seven mice display behavioral changes characteristic of tonic-clonic activity

• at 9 weeks, three of seven mice display behavioral changes characteristic of tonic-clonic activity

abnormal spike wave discharge ( J:149829 )

• mice exhibit isolated interictal spikes, short trains of repetitive spike lasting less than 5 seconds and long runs of repetitive spikes lasting between 5 and 10 seconds

• spike waves are more frequent at 9 weeks than at 6 weeks

• however, treatment with rapamycin reduces the severity of electrographic abnormalities

hydrocephaly ( J:75500 )

• often see hydrocephalus of the lateral ventricles

increased brain size ( J:75500 , J:149829 )

• 43% increased in brain size at 10-14 weeks of age, but not at 4 weeks (J:75500)

• variable with apparent enlargement of cortical, hippocampal and cerebellar structures (J:149829)

abnormal hippocampus morphology ( J:75500 )

• prominent astrogliosis in the hippocampus and the sub-pial surface

abnormal dentate gyrus morphology ( J:75500 )

• disorganization of the dentate gyrus at 10 weeks of age, characterized by marked undulation of the granule-cell layer

• intercellular spaces between granule-cell bodies, containing thick neuronal dendrites and astrocytes are expanded

• granule cells of the dentate gyrus have a greater surface area (are enlarged)

abnormal hippocampus pyramidal cell layer ( J:75500 )

• sclerosis of the pyramidal cell layer of the CA3

decreased hippocampus pyramidal cell number ( J:75500 )

• reduction in pyramidal cell density of the cornu ammonis

hippocampal neuron degeneration ( J:75500 )

abnormal cerebellum morphology ( J:75500 )

• enlarged cerebellum

abnormal cerebellar foliation ( J:75500 )

• thickened cerebellar folia

abnormal cerebellum external granule cell layer morphology ( J:75500 )

• multifocal persistence of the external granular cell layer at the pial surface

abnormal Purkinje cell morphology ( J:75500 )

• those Purkinje cells remaining are atrophic or dysplastic as indicated by dendritic coarsening and axonal swelling

decreased Purkinje cell number ( J:75500 )

• partial loss of Purkinje cells

abnormal cerebellar granule cell morphology ( J:75500 )

• soma size is increased in granule neurons at 10 weeks of age

abnormal cerebellar molecular layer ( J:75500 )

• mutants exhibit heterotopic neuronal clusters scattered in the molecular layer

• the molecular layer is thickened, especially at sites of heterotopic lesions

• disorganization, dysplasia, gliosis and elevated myelination in the molecular layer

gliosis ( J:75500 )

• gliosis in the molecular layer

• astrogliosis is visible in close proximity to the affected heterotopic neurons in the cerebellum and in the hippocampus and the sub-pial surface

neuron hypertrophy ( J:149829 )

• cortical Pten-negative neurons are hypertrophic

• at P12, soma size of Pten-negative neurons is increased 1.7-fold compared with wild-type neurons

• adult Pten-negative neurons are larger than in wild-type mice

• however, Pten-negative pyramidal neurons do not exhibit an increase in size with age and treatment with rapamycin suppresses neuron hypertrophy

lethargy ( J:75500 )

• develop sudden lethargy at 9 weeks of age

ataxia ( J:75500 , J:149829 )

• 13 of 25 develop ataxia by 9 weeks of age (J:75500)