Phenotypes Associated with This Genotype

Genotype
MGI:6095155

• Allelic Composition: Tg(tetO-TARDBP*A315T)13Lmit/0; Tg(Thy1-tTA)6Lmit/0
• Genetic Background: involves: C57BL/6

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

behavior/neurological

abnormal spatial reference memory ( J:245760 )

• in the Morris water maze, 1 month old mice show a delay in memory acquisition and 3 month old mice completely fail to learn, with mice only rarely finding the hidden platform

• during probe trials of the Morris water maze, mice spend less time in the target quadrant than controls

• 3 month old mice treated with doxycycline to turn off transgene expression for 1 week exhibit a similar impairment in memory acquisition in the Morris water maze as untreated mice

decreased anxiety-related response ( J:245760 )

• in the elevated plus maze, 1 month old mice spend 3-fold and 3 month old mice spend 5-fold more time in the open area indicating reduced anxiety or disinhibition

• 3 month old mice remain close to the edges of the area at all times of exploration in the open field

abnormal impulsive behavior control ( J:245760 )

• in the elevated plus maze, 1 month old mice spend 3-fold and 3 month old mice spend 5-fold more time in the open area indicating reduced anxiety or disinhibition

• 3 month old mice treated with doxycycline to turn off transgene expression for 1 week spend a similar amount of time in the open arms of the elevated plus maze as controls

impaired coordination ( J:245760 )

• 3 month, but not 1 month, old mice show a delay in turning at the top and reaching the bottom of a vertical pole, indicating impaired motor coordination

• 3 month, but not 1 month, old mice exhibit reduced latency to fall off the rotating rod during accelerated rotarod testing

• 3 month old mice treated with doxycycline to turn off transgene expression for 1 week are able to stay on the accelerating rotarod

decreased grip strength ( J:245760 )

• 4.5 month old mice exhibit reduced grip strength

increased locomotor activity ( J:245760 )

• when exposed to a novel environment in the open field, 3 month old mice show increased distance travelled reflecting higher speed than controls

• 3 month old mice treated with doxycycline to turn off transgene expression for 1 week no longer exhibit hyperactivity in the open field

nervous system

abnormal brain morphology ( J:242322 )

• loss of insoluble heterogeneous nuclear ribonucleoprotein K in the brain

abnormal hippocampus CA1 region morphology ( J:245760 )

• gradual loss of total CA1 neurons

small hippocampus ( J:245760 )

• hippocampal structure is already smaller at 2 weeks of age and the size of the hippocampus does not decrease significantly more until 4.5 months of age

abnormal primary motor cortex morphology ( J:245760 )

• progressive thinning of the motor cortex

loss of cortex neurons ( J:245760 )

• numbers of transgene-expressing neurons in layer V progressively decrease and those in layers II/III of the cortex increase

• number of POU3F2-positive neurons is reduced progressively in layer V

thin cerebral cortex ( J:245760 )

• cortical width progressively reduces over time

forebrain atrophy ( J:245760 )

• 6 month old mice show global forebrain atrophy, with a 21.2% reduced total brain volume

• 3 month old mice treated with doxycycline to turn off transgene expression for 1 week exhibit a comparable degree of brain atrophy as untreated mice

astrocytosis ( J:245760 )

• large numbers of tufted enlarged GFAP+ astrocytes are seen in all neuronal layers of the motor cortex at 1 month of age, with astrocyte activation persisting over time

• 3 month old mice treated with doxycycline to turn off transgene expression for 1 week show reversal of the astrogliosis in the cortex

• however, microglial activation is not observed

neuronal cytoplasmic inclusions ( J:245760 )

• some alpha-motor neurons show dense cytoplasmic TARDBP staining at 4.5 months of age resembling inclusions

neurodegeneration ( J:245760 )

• progressive hippocampal and cortical degeneration

hippocampal neuron degeneration ( J:245760 )

• degeneration of the hippocampus by 4 weeks of age

muscle

skeletal muscle atrophy ( J:245760 )

• skeletal muscle shows progressive degeneration, with increased numbers of small caliber fibers after 1 month of age

• 3 month old mice treated with doxycycline to turn off transgene expression for 1 week still exhibit muscle atrophy

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
amyotrophic lateral sclerosis type 10		DOID:0060201	OMIM:612069	J:242322 , J:245760