Phenotypes Associated with This Genotype

Genotype
MGI:5647883

• Allelic Composition: Lmx1a^tm1Tpe/Lmx1a^tm1Tpe; Lmx1b^tm1Zfc/Lmx1b^tm1Zfc; Slc6a3^tm1(cre)Lrsn/Slc6a3⁺
• Genetic Background: involves: 129S1/Sv * 129S7/SvEvBrd * 129X1/SvJ * C57BL/6

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

behavior/neurological

impaired short-term object recognition memory ( J:222854 )

• novel object recognition test indicates impaired short-term memory formation in adult and aged mice

• however, no differences are seen in anxiety or depression-like tests

impaired coordination ( J:222854 )

• impaired motor coordination in the pole test at 6 months of age and in the beam traversal and pole test at 18 months of age

increased locomotor activity ( J:222854 )

• in the open field, mice show a modest increase in locomotor activity at 18, but not 6, months of age

nervous system

abnormal innervation ( J:222854 )

• midbrain dopamine neuron innervation is impaired

• treatment with rapamycin almost completely normalizes the reduced striatal TH innervation

abnormal synaptic bouton morphology ( J:222854 )

• 3 month old mice exhibit abnormal nerve terminals in the striatum, with a 50% reduction in the density of TH-positive nerve terminals and abnormally large nerve terminals that reach up to 22 um in diameter frequently throughout the dorsal and ventral striatum

• enlarged presynaptic boutons show fewer synaptic vesicles at active zones and are filled with vacuoles and multilamellar autophagic-lysosomal vesicles that sometimes contain mitochondria

• 23% lower occurrence of synaptic active zones

• treatment with rapamycin alleviates the occurrence of abnormally large TH+ boutons in the striatum

abnormal synapse morphology ( J:222854 )

• synaptic morphology is disrupted in presynaptic midbrain dopamine neuron terminals

abnormal synaptic vesicle number ( J:222854 )

• enlarged presynaptic boutons show fewer synaptic vesicles at active zones

neurodegeneration ( J:222854 )

• progressive loss of TH-positive neurons in the ventral midbrain, with degenerating TH+ neurons frequently seen in young mice; reduction is seen within both the dorsal and ventral striatum

• dopamine transporter (DAT) expression is reduced, showing a modest reduction in young mice but a significant reduction in aged mice, indicating dopaminergic neuron degeneration

enhanced long-term potentiation ( J:222854 )

• mice exhibit enhanced induced LTP of Shaffer collateral-CA1 pyramidal cell synapses

• however, basal synaptic transmission is normal

taste/olfaction

impaired olfaction ( J:222854 )

• social olfaction is impaired in adult (6 months) and aged (18 months) mice

cellular

abnormal lysosome morphology ( J:222854 )

• accumulation of lysosomes in axonal terminals of midbrain dopamine neurons

abnormal autophagy ( J:222854 )

• accumulation of autophagosomes in axonal terminals of midbrain dopamine neurons

abnormal lysosome physiology ( J:222854 )

• the number of lipofuscin granules are reduced in midbrain dopamine neurons

• accumulation of electron-dense protein aggregates in midbrain dopamine neuron cell bodies

homeostasis/metabolism

abnormal autophagy ( J:222854 )

• accumulation of autophagosomes in axonal terminals of midbrain dopamine neurons

decreased dopamine level ( J:222854 )

• dopamine and its metabolites are reduced in brain areas such as prefrontal cortex, hippocampus, dorsal striatum, nucleus accumbens, substantia nigra and the ventral tegmental area

• however, levels are not reduced in the olfactory bulb or the cerebellum

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Parkinson's disease		DOID:14330	OMIM:PS168600	J:222854