Phenotypes for Th MGI:8253065 MGI Mouse

dystonia ( J:373014 , J:373408 )

• mice exhibit abnormal involuntary movements that are dynamic, not fixed postures, indicative of dystonia (J:373014)

• diurnal fluctuation is seen in dystonic movements (J:373014)

• forelimbs are often tucked tightly into the chest while hindlimbs are lifted off the cage floor in a stereotyped paddling motion with toes spread (J:373014)

• movements are comprised largely of flexion of the forelimbs, hindlimbs, and lower trunk and occasionally, the trunk is pressed down into the cage floor (J:373014)

• abnormal movements are sometimes seen at the start of the active (dark) period (8 pm) and increase throughout the night with the highest occurrence at the start of the inactive (light) period (8 am) (J:373014)

• peripheral administration of L-DOPA nearly abolishes the abnormal movements (J:373014)

• mice treated with trihexyphenidyl, a non-selective muscarinic acetylcholine receptor agonist, show a dose-dependent reduction in the abnormal movements (J:373014)

• microinjection of L-DOPA into the dorsal striatum, but not into the midline cerebellar vermis, reduces the abnormal movements (J:373014)

• L-DOPS administration has no effect on the abnormal movements (J:373014)

• mice show a dose-dependent increase in abnormal movements in response to both D1DAR antagonist SCH 23390 and the D2DAR antagonist raclopride (J:373014)

• administration of the D1DAR agonist SKF 81297 shows a trend towards reducing the abnormal movements and the D2DAR agonist quinpirole reduces the abnormal movements (J:373014)

• abnormal dystonic movements, including tonic flexion or extension, and clonic movements, increase during adolescence, peak at 2.5-4 months of age, and ebb in 12- and 15-month-old mice (J:373408)

• administration of daily L-dopa treatments throughout life abolishes abnormal movements in 15-month-old mice (J:373408)

• abnormal movements are reduced by both the D1-type dopamine receptor (D1R) agonist SKF 81297 and the D2-type dopamine receptor agonist quinpirole (J:373408)

impaired coordination ( J:373014 )

• mice show impairments on the rotarod and pole tests at 8 am but not at 8 pm

• peripheral administration of L-DOPA rescues the performance on the rotarod and pole test

abnormal voluntary movement ( J:373408 )

• mice show increased latency in the ability to escape an imposed abnormal posture, with a mean latency to move of approximately 12 seconds at 3 months of age and approximately 28 seconds at 15 months of age compared to controls which immediately escape, indicating a deficit in the ability to initiate voluntary movement

• L-Dopa treatment abolishes the deficit in the ability to initiate voluntary movement

decreased locomotor activity ( J:373014 , J:373408 )

• mice exhibit a normal circadian rhythm with an increase in locomotor activity at the start of the active period but this is followed by a rapid decline to below normal levels throughout the night; the reduction in locomotor activity is most pronounced during the last 6 hours of the active period, when dystonic movements are most severe (J:373014)

• mice challenged with amphetamine (to cause monoamine release from synaptic terminals) show a reduced increase in locomotor activity than wild-type mice (J:373014)

• while 1-month-old mice are hyperactive, mice show locomotor activity that is similar to controls until 12 months of age, after which mice exhibit a reduction in locomotor activity compared to controls, indicating a decrease in locomotor activity with age (J:373408)

• locomotor response to amphetamine (which stimulates presynaptic dopamine release), is comparable in young and aged mice instead of being increased at 3 months and decreased at 15 months as in controls, indicating that a change in presynaptic dopaminergic tone does not account for the reduction in locomotor activity and deficit in the ability to initiate movement in aged mice (J:373408)

hyperactivity ( J:373408 )

• 1-month-old mice are hyperactive

bradykinesia ( J:373408 )

• hypokinetic motor dysfunction in aged mice

decreased nervous system dopamine level ( J:373014 )

• dopamine levels are reduced in striatum, midbrain, and cortex and DOPAC, a metabolite of dopamine, is reduced

• the DOPAC/dopamine ratio is nearly 4-fold higher in the midbrain and striatum, suggesting that dopamine turnover occurs at a higher rate

• males exhibit a higher DOPC/dopamine ratio than females in the midbrain

• L-DOPA administration increases dopamine concentrations throughout the brain; striatal dopamine is repleted to only 22% of normal striatal dopamine concentrations

• striatal dopamine concentration is not elevated at 8 am as it is in wild-type mice and mice show a trend towards reduced dopamine at this time

• DOPAC concentrations are 3-fold higher at 8 pm than at 8 am compared to in wild-type mice which show lower levels at 8 pm than 8 am

• 375% increase in the ratio of striatal DOPAC/dopamine ratio at 8 pm compared to wild-type mice at 8 pm and compared to both mutant and wild-type mice at 8 am indicating enhanced dopamine turnover at 8 pm

decreased noradrenaline level ( J:373014 )

• norepinephrine concentrations are reduced throughout the brain, with the exception of the brainstem

• administration of either L-DOPA or L-DOPS increases norepinephrine concentrations throughout the brain

increased serotonin level ( J:373014 )

• 5-HT is increased in the brainstem

• 5-HIAA/5-HT ratio is increased in most brain regions

abnormal enzyme/coenzyme activity ( J:373014 )

• L-DOPA accumulation is reduced to approximately 15% of normal in the midbrain, the cortex, and cerebellum after inhibition of aromatic amino acid decarboxylase by NSD-1015 indicating reduced brain tyrosine hydroxylase activity, while it was only about 1% of normal in striatum

nervous system phenotype ( J:373408 )

N	• no difference in the number of midbrain TH+ (dopaminergic) neurons between aged control and mutant mice and no overt neurodegeneration is seen in 15-month-old mice