Phenotypes Associated with This Genotype

Genotype
MGI:3802584

• Allelic Composition: Tsc1^tm1Djk/Tsc1^tm1Djk; Tg(GFAP-cre)8Gtm/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * CBA

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

premature death ( J:167241 )

• premature death

• die by 18 weeks

growth/size/body

slow postnatal weight gain ( J:167241 )

• poor weight gain

nervous system

nervous system phenotype ( J:134889 )

N • low frequency glutamatergic synaptic transmission is normal in mutants

seizures ( J:116872 , J:167241 )

• hippocampal slices exposed to aCSF containing 6.5 mM potassium exhibited spontaneous interictal epileptiform bursting at a higher frequency than control slices (J:116872)

• occasional seizures at 4 weeks of age (J:167241)

increased neuron apoptosis ( J:134889 )

• at 1 and 3 months, higher numbers of apoptotic cells are detected in neocortex, CA1 and CA3 pyramidal cell layers and dentate gyrus (granular and subgranular layers) compared to control brains

increased brain size ( J:167241 )

• gross, generalized megencephaly

increased brain weight ( J:167241 )

• increased brain weight starting at 3 weeks of age

• become progressively more obvious with time

abnormal hippocampus pyramidal cell morphology ( J:167241 )

• progressive neuronal disorganization in hippocampus with a dispersion of the pyramidal cell layer

• greater CA1 pyramidal cell layer width in hippocampus

astrocytosis ( J:167241 )

• increased astrocyte number in neocortex beyond 3 weeks of age

• increased astrocyte number in hippocampus beyond 1 weeks of age

abnormal astrocyte physiology ( J:134889 )

• glutamate transport by astrocytes is impaired, resulting in elevated extracellular fluid glutamate (ECF) concentrations in the hippocampus at 4 weeks of age

abnormal single cell response ( J:116872 )

• astrocytes have significantly lower peak barium-sensitive current in response to neuronal activation than controls

• barium-sensitive inwardly rectifying potassium currents in cultured astrocytes show reduced amplitudes at all hyper- and depolarizing voltages used for stimulation compared with wild-type neurons; similarly currents in glia in tissue slices are reduced in response to voltage steps

• barium-sensitive conductances are lower in Tsc1-null neurons relative to wild-type

reduced long-term potentiation ( J:134889 )

• LTP induced by tetanic stimulation is significantly decreased compared to controls

• this effect is partially reversed by partial blockade of NMDA receptors with D-APV

behavior/neurological

behavior/neurological phenotype ( J:134889 )

N • despite coordiation defects, mice are not impaired in wide variety of other tests of motor/sensorimotor function

abnormal associative learning ( J:134889 )

• in conditioning chamber tests with tone/shock (T/S) pairings, mutants show impaired short term context conditioning compared to controls on day 1 of training

abnormal contextual conditioning behavior ( J:134889 )

• when placed in chamber 24 hours after T/S training, mice show virtually no freezing indicating impaired contextual fear conditioning compared to controls

• control mice show habituation, displaying decreased freezing time, whereas mutants show potentiation of freezing

abnormal cued conditioning behavior ( J:134889 )

• 24 hours after contextual fear testing, mutants show less freezing behavior in response to auditory tone compared to controls

abnormal spatial learning ( J:134889 )

• mutants at P32 show impaired spatial learning in Morris water maze tests

impaired coordination ( J:134889 )

• mice exhibit significantly increased times to climb down pole in pole test

impaired swimming ( J:134889 )

• reduced swimming speed in Morris water maze trials

seizures ( J:116872 , J:167241 )

• hippocampal slices exposed to aCSF containing 6.5 mM potassium exhibited spontaneous interictal epileptiform bursting at a higher frequency than control slices (J:116872)

• occasional seizures at 4 weeks of age (J:167241)

cellular

increased neuron apoptosis ( J:134889 )

• at 1 and 3 months, higher numbers of apoptotic cells are detected in neocortex, CA1 and CA3 pyramidal cell layers and dentate gyrus (granular and subgranular layers) compared to control brains

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
tuberous sclerosis		DOID:13515	OMIM:PS191100	J:134889 , J:167241