Phenotypes associated with this allele

• Allele Symbol: Slc6a3^tm1(cre)Lrsn
• Allele Name: targeted mutation 1, Nils-Goran Larsson
• Allele ID: MGI:3702746
• Summary: 9 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Gt(ROSA)26Sor^tm1Lrsn/Gt(ROSA)26Sor^+ Prkn^tm1Roo/Prkn^tm1Roo Slc6a3^tm1(cre)Lrsn/Slc6a3^+ Tfam^tm1Lrsn/Tfam^tm1Lrsn	involves: 129S1/Sv * 129S2/SvPas * 129X1/SvJ * C57BL/6	MGI:5292517
cn2	Slc6a3^tm1(cre)Lrsn/Slc6a3^+ Snca^tm1Nbm/Snca^tm1Nbm Tfam^tm1Lrsn/Tfam^tm1Lrsn	involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ * C57BL/6 * SJL	MGI:3702933
cn3	Lmx1a^tm1Tpe/Lmx1a^tm1Tpe Lmx1b^tm1Zfc/Lmx1b^tm1Zfc Slc6a3^tm1(cre)Lrsn/Slc6a3^+	involves: 129S1/Sv * 129S7/SvEvBrd * 129X1/SvJ * C57BL/6	MGI:5647883
cn4	Mfn1^tm1.1Arte/Mfn1^tm1.1Arte Slc6a3^tm1(cre)Lrsn/Slc6a3^+	involves: 129S1/Sv * 129X1/SvJ	MGI:5440840
cn5	Nr4a2^tm1.1Pcn/Nr4a2^tm1.1Pcn Slc6a3^tm1(cre)Lrsn/Slc6a3^tm1(cre)Lrsn	involves: 129S1/Sv * 129X1/SvJ	MGI:4437054
cn6	Mfn2^tm1.1Arte/Mfn2^tm1.1Arte Slc6a3^tm1(cre)Lrsn/Slc6a3^+	involves: 129S1/Sv * 129X1/SvJ	MGI:5440841
cn7	Gt(ROSA)26Sor^tm1Lrsn/Gt(ROSA)26Sor^+ Mfn2^tm1.1Arte/Mfn2^tm1.1Arte Slc6a3^tm1(cre)Lrsn/Slc6a3^+	involves: 129S1/Sv * 129X1/SvJ	MGI:5440842
cn8	Gt(ROSA)26Sor^tm1Lrsn/Gt(ROSA)26Sor^+ Slc6a3^tm1(cre)Lrsn/Slc6a3^+ Tfam^tm1Lrsn/Tfam^tm1Lrsn	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5292515
cn9	Slc6a3^tm1(cre)Lrsn/Slc6a3^+ Tfam^tm1Lrsn/Tfam^tm1Lrsn	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL	MGI:3702932

Genotype
MGI:5292517

cn1

• Allelic Composition: Gt(ROSA)26Sor^tm1Lrsn/Gt(ROSA)26Sor⁺; Prkn^tm1Roo/Prkn^tm1Roo; Slc6a3^tm1(cre)Lrsn/Slc6a3⁺; Tfam^tm1Lrsn/Tfam^tm1Lrsn
• Genetic Background: involves: 129S1/Sv * 129S2/SvPas * 129X1/SvJ * C57BL/6

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

nervous system

abnormal neuron morphology ( J:176022 )

• YFP+ neurons exhibit one or more grossly enlarged, rounded mitochondria in the perinuclear region of the soma and in proximal segment of dendrites with some cells containing fragmented mitochondria and small, spherical mitochondrial clustered around the nucleus

• YFP+ neurons exhibit a progressive reduction in distal axonal mitochondrial numbers compared with control cells

• however, mitochondria in the distal dopamine axons are morphologically spared

loss of dopaminergic neurons ( J:176022 )

abnormal axonal transport ( J:176022 )

• neurons exhibit less intense staining with a retrograde tracer (fluorogold) suggesting impaired retrograde transport and/or uptake of the tracer compared with control cells

Genotype
MGI:3702933

cn2

• Allelic Composition: Slc6a3^tm1(cre)Lrsn/Slc6a3⁺; Snca^tm1Nbm/Snca^tm1Nbm; Tfam^tm1Lrsn/Tfam^tm1Lrsn
• Genetic Background: involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ * C57BL/6 * SJL

nervous system

neuronal intranuclear inclusions ( J:119515 )

• triple mutants show same phenotype as Tfam^tm1Lrsn, Slc6a3^tm1(cre)Lrsn mice; neuronal inclusions remain indicating that additional lack of Snca is not required for develoment of the Parkonsonian phenotype

Genotype
MGI:5647883

cn3

• 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

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

Genotype
MGI:5440840

cn4

• Allelic Composition: Mfn1^tm1.1Arte/Mfn1^tm1.1Arte; Slc6a3^tm1(cre)Lrsn/Slc6a3⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

normal phenotype

no abnormal phenotype detected ( J:188337 )

• viable with normal locomotor activity and body weight

Genotype
MGI:4437054

cn5

• Allelic Composition: Nr4a2^tm1.1Pcn/Nr4a2^tm1.1Pcn; Slc6a3^tm1(cre)Lrsn/Slc6a3^tm1(cre)Lrsn
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

mortality/aging

lethality at weaning, complete penetrance ( J:157098 )

• mice do not survive beyond 3 weeks

• however, leaving pups with mothers improves perinatal survival beyond 3 weeks

nervous system

abnormal dopaminergic neuron morphology ( J:157098 )

• expression of midbrain dopamine neuron markers is lost compared to in wild-type mice

neuron degeneration ( J:157098 )

• mice exhibit a rapid loss of substantia nigra pars compacta cell bodies with only scattered ventral tegmental area neurons remaining compared with wild-type mice

behavior/neurological

decreased vertical activity ( J:157098 )

• at 4 and 14 months

decreased locomotor activity ( J:157098 )

hyperactivity ( J:157098 )

• L-DOPA-treated mice exhibit hyperactivity unlike similarly treated wild-type mice

increased stereotypic behavior ( J:157098 )

• L-DOPA-treated mice exhibit repetitive behaviors (including repetitive gnawing, excessive grooming, and self-injury) unlike similarly treated wild-type mice

homeostasis/metabolism

decreased dopamine level ( J:157098 )

• at P1, striatal dopamine levels are decreased to 14% of wild-type

• at P14, the ratio of homovanillic acid (HVA) to dopamine is increased indicating increased dopamine turnover compared to in wild-type mice

• at P60, striatal dopamine levels are almost completely lost unlike in wild-type mice

• at P60, dopamine levels are more severely decreased in the caudate putamen compared to in the nucleus accumbens

increased serotonin level ( J:157098 )

• serotonin levels in the caudate putamen and nucleus accumbens are increased compared to in wild-type mice

abnormal response/metabolism to endogenous compounds ( J:157098 )

• L-DOPA-treated mice exhibit hyperactivity and repetitive behaviors unlike similarly treated wild-type mice

growth/size/body

decreased body size ( J:157098 )

• at 2 months, mice left with their mothers after weaning are 40% smaller than wild-type mice

Genotype
MGI:5440841

cn6

• Allelic Composition: Mfn2^tm1.1Arte/Mfn2^tm1.1Arte; Slc6a3^tm1(cre)Lrsn/Slc6a3⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

mortality/aging

premature death ( J:188337 )

• die before 7 weeks of age with a median survival of 5.8 weeks

• life span can be increased to 11-12 weeks of age when provided with moist food on the cage floor

nervous system

abnormal substantia nigra pars compacta morphology ( J:188337 )

• pathological alterations (irregular margins and elongated nuclei) of the somata of the substantia nigra pars compacta are seen at 5 weeks of age

abnormal innervation ( J:188337 )

• profound lack of dopaminergic neuron innervation in the striatum

abnormal neuron physiology ( J:188337 )

• severe respiratory chain deficiency in mitochondria in dopaminergic neurons

growth/size/body

decreased body weight ( J:188337 )

• at 5 weeks of age

weight loss ( J:188337 )

• continue to lose weight even when provided with moist food on the cage floor

behavior/neurological

abnormal locomotor activation ( J:188337 )

• total distance traveled is significantly increased in an open field test

• however, locomotion as assessed by horizontal beam breaks is similar to controls

decreased vertical activity ( J:188337 )

• decreased rearing activity in an open field test

decreased locomotor activity ( J:188337 )

• become severely hypokinetic with age

cellular

abnormal respiratory electron transport chain ( J:188337 )

• severe respiratory chain deficiency in mitochondria in dopaminergic neurons

homeostasis/metabolism

decreased dopamine level ( J:188337 )

• severe reduction in the striatum at 5 weeks of age

• also reduced in the substantia nigra pars compacta

increased serotonin level ( J:188337 )

• in the striatum

Genotype
MGI:5440842

cn7

• Allelic Composition: Gt(ROSA)26Sor^tm1Lrsn/Gt(ROSA)26Sor⁺; Mfn2^tm1.1Arte/Mfn2^tm1.1Arte; Slc6a3^tm1(cre)Lrsn/Slc6a3⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

nervous system

abnormal dorsal striatum morphology ( J:188337 )

• profound reduction in the number of labeled mitochondria in the dorsal striatum

abnormal dopaminergic neuron morphology ( J:188337 )

• mitochondria are spherical and enlarged with disorganized cristae

cellular

abnormal mitochondrial shape ( J:188337 )

• mitochondria in dopaminergic neurons are spherical and enlarged with disorganized cristae

decreased mitochondrial number ( J:188337 )

• profound reduction in the number of labeled mitochondria in the dorsal striatum

increased mitochondrial size ( J:188337 )

• mitochondria in dopaminergic neurons are spherical and enlarged with disorganized cristae

Genotype
MGI:5292515

cn8

• Allelic Composition: Gt(ROSA)26Sor^tm1Lrsn/Gt(ROSA)26Sor⁺; Slc6a3^tm1(cre)Lrsn/Slc6a3⁺; Tfam^tm1Lrsn/Tfam^tm1Lrsn
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

Mitochondria abnormalities in Tfam^tm1Lrsn/Tfam^tm1Lrsn Slc6a3^tm1(cre)Lrsn/Slc6a3⁺ Gt(ROSA)26Sor^tm1Lrsn/Gt(ROSA)26Sor⁺ neurons

nervous system

abnormal neuron morphology ( J:176022 )

• YFP+ neurons exhibit one or more grossly enlarged, rounded mitochondria in the perinuclear region of the soma and in proximal segment of dendrites with some cells containing fragmented mitochondria and small, spherical mitochondrial clustered around the nucleus

• YFP+ neurons exhibit a progressive reduction in distal axonal mitochondrial numbers compared with control cells

loss of dopaminergic neurons ( J:176022 )

cellular

abnormal mitochondrial physiology ( J:176022 )

• smaller mitochondrial and the largest aggregates in a rare number of neurons exhibit reduced import competence compared with mitochondria in control cells

behavior/neurological

abnormal locomotor behavior ( J:176022 )

• impaired from 20 weeks of age

growth/size/body

weight loss ( J:176022 )

• from 20 weeks of age

muscle

muscle hypertonia ( J:176022 )

• rigidity from 20 weeks of age

Genotype
MGI:3702932

cn9

• Allelic Composition: Slc6a3^tm1(cre)Lrsn/Slc6a3⁺; Tfam^tm1Lrsn/Tfam^tm1Lrsn
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

mortality/aging

premature death ( J:119515 )

• mutants have to be terminated at ~45 weeks due to poor general condition

behavior/neurological

decreased exploration in new environment ( J:119515 )

• mice aged 14-15 weeks display decreased exploratory activity

tremors ( J:119515 )

• progressive Parkinsonian symptoms are observed, with tremor observed at 20 weeks of age

abnormal limb posture ( J:119515 )

• apparent limb rigidity is observed at 20 weeks of age

decreased locomotor activity ( J:119515 )

nervous system

abnormal dopaminergic neuron morphology ( J:119515 )

• majority of neurons contain small cytoplasmic aggregates, detected at 6 weeks through 43 weeks

• inclusions are present in most dopaminergic midbrain neurons and the mean size increased as the neurodegeneration progressed

• large, partially electron-dense bodies located in dendritic structures close to neuronal somata are observed at 11 weeks; some of these bodies have an amorphous content with a diffuse lining, while others display tubular formations and have distinct double layer membranes which are ultrastructurally typical of mitochondrial membranes

loss of dopaminergic neurons ( J:119515 )

• dopaminergic (DA) neuron loss is observed in the dorsolateral striatum at 12 weeks of age, progressing to involve most of the dorsal and ventral striatum with age

• tyrosine hydroxylase-expressing midbrain neurons show a slow progressive cell loss, which is more marked and starts sooner in the substantia nigra compared to the ventral tegmental area

neuronal intranuclear inclusions ( J:119515 )

muscle

muscle spasm ( J:119515 )

• twitching is observed at 20 weeks of age

homeostasis/metabolism

decreased dopamine level ( J:119515 )

• neuron loss results in loss of dopamine in the nigrostriatal system in 20-week old mice

• there are markedly increased ratios of dopamine metabolites to dopamine in the striatum at 20 weeks

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Parkinson's disease		DOID:14330	OMIM:PS168600	J:119515