All Phenotypes Th<tm1.1Ehess> MGI Mouse

dystonia ( J:373014 )

• mice exhibit abnormal involuntary movements that are dynamic, not fixed postures, indicative of dystonia

• diurnal fluctuation is seen in dystonic movements

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

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

• 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)

• peripheral administration of L-DOPA nearly abolishes the abnormal movements

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

• microinjection of L-DOPA into the dorsal striatum, but not into the midline cerebellar vermis, reduces the abnormal movements

• L-DOPS administration has no effect on the abnormal movements

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

• administration of the D1DAR agonist SKF 81297 shows a trend towards reducing the abnormal movements and the D2DAR agonist quinpirole reduces the abnormal movements

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

decreased locomotor activity ( J:373014 )

• 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

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