Phenotypes associated with this allele

• Allele Symbol: Slc6a3^{tm1.1(cre)Bkmn}
• Allele Name: targeted mutation 1.1, Cristina M Backman
• Allele ID: MGI:3689434
• Summary: 11 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Slc6a3^tm1.1(cre)Bkmn/Slc6a3^tm1.1(cre)Bkmn	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:3689567
cn2	Cox10^tm1Ctm/Cox10^tm1Ctm Slc6a3^tm1.1(cre)Bkmn/?	B6.Cg-Cox10^tm1Ctm Slc6a3^tm1.1(cre)Bkmn	MGI:5775427
cn3	Drd2^tm1.1Mrub/Drd2^tm1.1Mrub Slc6a3^tm1.1(cre)Bkmn/Slc6a3^+	B6.Cg-Drd2^tm1.1Mrub Slc6a3^tm1.1(cre)Bkmn	MGI:5292386
cn4	Gt(ROSA)26Sor^tm1.1(CAG-COX8A/Dendra2)Dcc/Gt(ROSA)26Sor^+ Mfn2^tm3Dcc/Mfn2^tm3Dcc Slc6a3^tm1.1(cre)Bkmn/Slc6a3^+	involves: 129 * 129S6/SvEvTac * C57BL/6J * SJL/J	MGI:5441517
cn5	Gt(ROSA)26Sor^tm1.1(CAG-COX8A/Dendra2)Dcc/Gt(ROSA)26Sor^+ Mfn1^tm2Dcc/Mfn1^tm2Dcc Slc6a3^tm1.1(cre)Bkmn/Slc6a3^+	involves: 129 * 129S6/SvEvTac * C57BL/6J * SJL/J	MGI:5441518
cn6	Otx2^tm6Asim/Otx2^tm11Asim Slc6a3^tm1.1(cre)Bkmn/Slc6a3^+	involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ	MGI:4887467
cn7	Gt(ROSA)26Sor^tm1.1(Otx2)Daac/Gt(ROSA)26Sor^tm1.1(Otx2)Daac Slc6a3^tm1.1(cre)Bkmn/Slc6a3^+	involves: 129P2/OlaHsd * C57BL/6 * DBA/2	MGI:4887464
cn8	Gt(ROSA)26Sor^tm1.1(Otx2)Daac/Gt(ROSA)26Sor^+ Slc6a3^tm1.1(cre)Bkmn/Slc6a3^+	involves: 129P2/OlaHsd * C57BL/6 * DBA/2	MGI:4887465
cn9	Gt(ROSA)26Sor^tm1.1(Otx2)Daac/Gt(ROSA)26Sor^tm1.1(Otx2)Daac Slc6a3^tm1.1(cre)Bkmn/Slc6a3^+ Tg(CAG-Otx2,-GFP)21Asim/0	involves: 129P2/OlaHsd * C57BL/6 * DBA/2	MGI:4887466
cn10	Pten^tm1Hwu/Pten^tm1Hwu Slc6a3^tm1.1(cre)Bkmn/Slc6a3^+	involves: 129S4/SvJae * C57BL/6	MGI:4849440
cn11	Kcnj6^em1.1Ktaka/Kcnj6^em1.1Ktaka Slc6a3^tm1.1(cre)Bkmn/Slc6a3^+	involves: C57BL/6J * C57BL/6N	MGI:6144037

Genotype
MGI:3689567

hm1

• Allelic Composition: Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3^{tm1.1(cre)Bkmn}
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

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

normal phenotype

no abnormal phenotype detected ( J:114466 )

• homozygous and heterozygous mice are normal and viable

Genotype
MGI:5775427

cn2

• Allelic Composition: Cox10^tm1Ctm/Cox10^tm1Ctm; Slc6a3^{tm1.1(cre)Bkmn}/?
• Genetic Background: B6.Cg-Cox10^tm1Ctm Slc6a3^{tm1.1(cre)Bkmn}

behavior/neurological

abnormal motor capabilities/coordination/movement ( J:231810 )

• mice exhibit a decline in motor activity and coordination by 2 months of age, maximum decline is reached by 4 months of age

impaired coordination ( J:231810 )

• mice are not able to perform the pole test by 2 months of age, however, treatment with high dose L-DOPA (25 mg/kg) or pioglitazone improves performance

• impaired rotarod performance by 2 months of age, however, treatment with high dose L-DOPA (25 mg/kg) or pioglitazone improves performance

• walking time is decreased on rotarod at 4 and 6 months as compared to younger animals

decreased vertical activity ( J:231810 )

• decrease in rearing activity by 2 months of age, maximum decline is reached by 4 months of age

decreased locomotor activity ( J:231810 )

• mice move less during nocturnal cycle and in open field test (distance travelled) as compared to controls; treatment with high dose L-DOPA (25 mg/kg) results in hyperactivity and stereotypic movements

• maximum decline in motor performance is reached at 4 months of age

hematopoietic system

microgliosis ( J:231810 )

increased microglial cell activation ( J:231810 )

• activation of microglial cells in midbrain as detected by Iba1 immunoreactivity

• treatment with pioglitazone for 4 months results in reduction in Iba1 immunoreactivity in midbrain

growth/size/body

decreased body weight ( J:231810 )

• pups are born at a lower body weight than controls and remain at a lower weight throughout life

• administration of pioglitazone increases weight to control levels

immune system

microgliosis ( J:231810 )

increased microglial cell activation ( J:231810 )

• activation of microglial cells in midbrain as detected by Iba1 immunoreactivity

• treatment with pioglitazone for 4 months results in reduction in Iba1 immunoreactivity in midbrain

abnormal chemokine secretion ( J:231810 )

• CXCL10 and CCL2 are increased in striatum

• in midbrain, levels of IL6, IL10, CXCL10 and CCL2 trend upward, but do not reach significance

increased interleukin-1 beta secretion ( J:231810 )

• increase in IL1B in midbrain in 2 month old mice

• IL1B is slightly increased in striatum but does not reach significance

homeostasis/metabolism

decreased dopamine level ( J:231810 )

• decrease in dopamine and dopamine metabolites (to a lesser extent) in striatum by 2 months of age as compared to controls

• dopamine depletion continues through out life but does not worsen

nervous system

microgliosis ( J:231810 )

increased microglial cell activation ( J:231810 )

• activation of microglial cells in midbrain as detected by Iba1 immunoreactivity

• treatment with pioglitazone for 4 months results in reduction in Iba1 immunoreactivity in midbrain

decreased dopaminergic neuron number ( J:231810 )

loss of dopaminergic neurons ( J:231810 )

• substantial loss of dopaminergic cell bodies in the substantial nigra as measured by reduction of tyrosine hydroxylase (TH) and dopamine transporter (DAT) content

• widespread axonal degeneration in striatum

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Parkinson's disease		DOID:14330	OMIM:PS168600	J:231810

Genotype
MGI:5292386

cn3

• Allelic Composition: Drd2^tm1.1Mrub/Drd2^tm1.1Mrub; Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3⁺
• Genetic Background: B6.Cg-Drd2^tm1.1Mrub Slc6a3^{tm1.1(cre)Bkmn}

behavior/neurological

enhanced behavioral response to cocaine ( J:176167 )

• locomotor activity is increased 1.4-fold at low doses in cocaine-treated mice unlike in similarly treated control mice

• at higher doses, cocaine-induced hyperactivity is 3.8-fold compared to 2.8-fold in similarly treated control mice

abnormal operant conditioning behavior ( J:176167 )

• mice exhibit increased motivation to work for food compared with control mice

• however, mice exhibit normal profile of loss of responding following cessation of reward delivery

hyperactivity ( J:176167 )

• in an open field that is insensitive to quinpirole treatment

• however, habituation is normal

induced hyperactivity ( J:176167 )

• locomotor activity is increased 1.4-fold at low doses in cocaine-treated mice unlike in similarly treated control mice

• at higher doses, cocaine-induced hyperactivity is 3.8-fold compared to 2.8-fold in similarly treated control mice

nervous system

abnormal single cell response ( J:176167 )

• quinpirole fails to induce a slow hyperpolarizing current in dopaminergic neurons unlike in similarly treated control cells

• however, response to baclofen is normal

abnormal inhibitory postsynaptic currents ( J:176167 )

• decreased and insensitive to sulpiride

abnormal synaptic dopamine release ( J:176167 )

• during train stimulation, mice exhibit supramaximal dopamine release that increases during stimulation that is insensitive to sulpiride unlike in control mice

homeostasis/metabolism

decreased physiological sensitivity to xenobiotic ( J:176167 )

• quinpirole fails to induce a slow hyperpolarizing current in dopaminergic neurons or reduce locomotor activity unlike in similarly treated control mice

• sulpiride fails to decreased inhibitory postsynaptic currents unlike in control cells

• tyrosine hydroxylase activity is insensitive to quinpirole unlike in control cells

• however, response to baclofen is normal

increased physiological sensitivity to xenobiotic ( J:176167 )

• mice treated with haloperidol exhibit greater decrease in locomotion compared with similarly treated control mice

Genotype
MGI:5441517

cn4

• Allelic Composition: Gt(ROSA)26Sor^{tm1.1(CAG-COX8A/Dendra2)Dcc}/Gt(ROSA)26Sor⁺; Mfn2^tm3Dcc/Mfn2^tm3Dcc; Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3⁺
• Genetic Background: involves: 129 * 129S6/SvEvTac * C57BL/6J * SJL/J

mortality/aging

premature death ( J:188347 )

• mutants die around 6-7 weeks of age due to malnutrition; this is most likely due to difficulty accessing food and water in normal cages due to a rearing defect

• however, when mutants are supplied with hydrated gel packs and crushed pieces of regular chow, all mutants survive beyond 6 months of age, with a majority surviving past 1 year of age

growth/size/body

decreased body size ( J:188347 )

• mutants are significantly smaller than controls by 5 weeks of age

decreased body weight ( J:188347 )

• mutants do not gain weight after 4 weeks of age

behavior/neurological

hunched posture ( J:188347 )

• mutants are hunched by 5 weeks of age

decreased vertical activity ( J:188347 )

• severe rearing defect as early as 4 weeks of age

• treatment of mutants with L-DOPA alleviates the motor defects

decreased locomotor activity ( J:188347 )

• mutants are hypoactive by 5 weeks of age

• at 4-5 weeks of age, mutants travel only 68% of the distance traveled by wild-type mice and by 8-11 weeks of age, the distance traveled reduces to 34% of wild-type, indicating an age-dependent decline in locomotive activity

bradykinesia ( J:188347 )

• beginning at 4-5 weeks, mutants exhibit progressive bradykinesia

• mutants exhibit a decline in the speed of movement with age compared to controls

• mutants spend twice as much time inactive at 6-7 weeks of age as controls and by 8-11 weeks of age, this increases to 6-fold increase in inactive time

nervous system

abnormal striatum morphology ( J:188347 )

• loss of dopaminergic terminals in the striatum, with a 25% reduction in dopaminergic terminals at 3 weeks of age and 76% reduction by 8-10 weeks

abnormal innervation ( J:188347 )

• mutants exhibit loss of dopaminergic efferents to the striatum, with a 25% reduction in dopaminergic terminals at 3 weeks of age and a 76% reduction by 8-10 weeks of age

• however, projections to the nucleus accumbens and olfactory tubercle are protected and the dopaminergic terminals are moderately preserved at 11-14 weeks

abnormal dopaminergic neuron morphology ( J:188347 )

• dopaminergic neurons remaining have smaller cell bodies and diminished neuronal processes

• dopaminergic neurons exhibit mitochondrial fragmentation and depletion

loss of dopaminergic neurons ( J:188347 )

• retrograde degeneration of substantia nigra pars compacta dopaminergic neurons and to a lesser extent in the mesolimbic pathway

neurodegeneration ( J:188347 )

• progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit, with neuronal loss first seen at 10-12 weeks, when a 52% decrease in TH-positive neurons is seen

• some degeneration is also seen in the mesolimbic pathway, although a lesser extent than in the nigrostriatal circuit

• degeneration of dopaminergic neurons occurs in a stepwise manner, with initial defects at the axon terminals, followed 1-2 months later by degeneration of the cell bodies

abnormal axonal transport ( J:188347 )

• mutants show decreased mitochondrial transport along nerve processes

cellular

abnormal mitochondrial morphology ( J:188347 )

• dopaminergic neurons exhibit mitochondrial fragmentation and depletion

skeleton

kyphosis ( J:188347 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Parkinson's disease		DOID:14330	OMIM:PS168600	J:188347

Genotype
MGI:5441518

cn5

• Allelic Composition: Gt(ROSA)26Sor^{tm1.1(CAG-COX8A/Dendra2)Dcc}/Gt(ROSA)26Sor⁺; Mfn1^tm2Dcc/Mfn1^tm2Dcc; Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3⁺
• Genetic Background: involves: 129 * 129S6/SvEvTac * C57BL/6J * SJL/J

normal phenotype

no abnormal phenotype detected ( J:188347 )

• mice show no abnormal phenotype up to 1 year of age

Genotype
MGI:4887467

cn6

• Allelic Composition: Otx2^tm6Asim/Otx2^tm11Asim; Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ

nervous system

increased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit reduced numbers of tyrosine hydroxylase (TH)+ neurons and GFP+ TH+ neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with similarly treated wild-type mice

abnormal neuron differentiation ( J:166896 )

• the percentage of GFP+ glyco-Slc6a3 (DAT)+ neurons is higher than in control mice

homeostasis/metabolism

increased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit reduced numbers of tyrosine hydroxylase (TH)+ neurons and GFP+ TH+ neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with similarly treated wild-type mice

cellular

increased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit reduced numbers of tyrosine hydroxylase (TH)+ neurons and GFP+ TH+ neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with similarly treated wild-type mice

abnormal neuron differentiation ( J:166896 )

• the percentage of GFP+ glyco-Slc6a3 (DAT)+ neurons is higher than in control mice

Genotype
MGI:4887464

cn7

• Allelic Composition: Gt(ROSA)26Sor^{tm1.1(Otx2)Daac}/Gt(ROSA)26Sor^{tm1.1(Otx2)Daac}; Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * DBA/2

nervous system

decreased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit increased number of tyrosine hydroxylase (TH)+ neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with Slc6a3^{tm1.1(cre)Bkmn} heterozygotes

decreased dopaminergic neuron number ( J:166896 )

• mice exhibit a reduction in the percentage of Kcnj6 (Girk2)+ or glyco-Slc6a3 (DAT)+ and tyrosine hydroxylase (TH)+ neurons in the ventral tegmental area (VTA) compared with wild-type mice

homeostasis/metabolism

decreased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit increased number of tyrosine hydroxylase (TH)+ neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with Slc6a3^{tm1.1(cre)Bkmn} heterozygotes

cellular

decreased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit increased number of tyrosine hydroxylase (TH)+ neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with Slc6a3^{tm1.1(cre)Bkmn} heterozygotes

Genotype
MGI:4887465

cn8

• Allelic Composition: Gt(ROSA)26Sor^{tm1.1(Otx2)Daac}/Gt(ROSA)26Sor⁺; Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * DBA/2

nervous system

decreased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit a modest increased number of tyrosine hydroxylase (TH)+ in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with Slc6a3^{tm1.1(cre)Bkmn} heterozygotes

homeostasis/metabolism

decreased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit a modest increased number of tyrosine hydroxylase (TH)+ in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with Slc6a3^{tm1.1(cre)Bkmn} heterozygotes

cellular

decreased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit a modest increased number of tyrosine hydroxylase (TH)+ in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with Slc6a3^{tm1.1(cre)Bkmn} heterozygotes

Genotype
MGI:4887466

cn9

• Allelic Composition: Gt(ROSA)26Sor^{tm1.1(Otx2)Daac}/Gt(ROSA)26Sor^{tm1.1(Otx2)Daac}; Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3⁺; Tg(CAG-Otx2,-GFP)21Asim/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * DBA/2

nervous system

decreased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit increased number of tyrosine hydroxylase (TH)+ neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with Slc6a3^{tm1.1(cre)Bkmn} heterozygotes

decreased dopaminergic neuron number ( J:166896 )

• mice exhibit a reduction in the percentage of Kcnj6 (Girk2)+ or glyco-Slc6a3 (DAT)+ and tyrosine hydroxylase (TH)+ neurons in the ventral tegmental area (VTA) compared with wild-type mice

homeostasis/metabolism

decreased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit increased number of tyrosine hydroxylase (TH)+ neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with Slc6a3^{tm1.1(cre)Bkmn} heterozygotes

cellular

decreased susceptibility to dopaminergic neuron neurotoxicity ( J:166896 )

• MPTP-treated mice exhibit increased number of tyrosine hydroxylase (TH)+ neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) compared with Slc6a3^{tm1.1(cre)Bkmn} heterozygotes

Genotype
MGI:4849440

cn10

• Allelic Composition: Pten^tm1Hwu/Pten^tm1Hwu; Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6

Altered dopamine neurons in the ventral midbrain of Pten^tm1Hwu/Pten^tm1Hwu Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3⁺ mice

behavior/neurological

behavior/neurological phenotype ( J:153622 )

N • no difference in locomotor activity is seen compared to controls during exposure to a novel environment

abnormal behavioral response to xenobiotic ( J:153622 )

• mutants exhibit a significant reduction in ipsilateral rotational behavior in response to amphetamine administration after 6OHDA lesioning

nervous system

abnormal midbrain morphology ( J:153622 )

• neuronal hypertrophy in the ventral midbrain resulting in enlargement of the ventral midbrain area

• increase in the number of TH positive neurons in the substantia nigra compacta and ventral tegmental area of the adult ventral midbrain and an increase in neuronal soma size

abnormal substantia nigra pars compacta morphology ( J:153622 )

• increase in the number of TH positive neurons in the substantia nigra compacta

abnormal substantia nigra pars reticulata morphology ( J:153622 )

• increase in the number of dopaminergic neuron dendritic processes in the substantia nigra pars reticulata

abnormal striatum morphology ( J:153622 )

• modest but significant enlargement of the caudal striatum

abnormal dopaminergic neuron morphology ( J:153622 )

• increase in number of dopaminergic neurons and fibers in the ventral mesencephalon

• dopaminergic neurons in the ventral midbrain are larger in size and have an increase in the number of dendritic processes in the substantia nigra pars reticulata

neuron hypertrophy ( J:153622 )

• hypertrophy of dopamine neurons

abnormal nervous system physiology ( J:153622 )

• mutant dopamine neurons are protected from 6OHDA induced lesions, fiber loss, and axonal loss in the striatum compared to controls

homeostasis/metabolism

increased dopamine level ( J:153622 )

• increase in total dopamine tissue levels in the dorsal striatum and midbrain, however, no alterations in basal dopamine extracellular levels or evoked dopamine release in the dorsal striatum

Genotype
MGI:6144037

cn11

• Allelic Composition: Kcnj6^em1.1Ktaka/Kcnj6^em1.1Ktaka; Slc6a3^{tm1.1(cre)Bkmn}/Slc6a3⁺
• Genetic Background: involves: C57BL/6J * C57BL/6N

behavior/neurological

behavioral despair ( J:257982 )

• mice show decreased immobility time in the forced swimming test

• however, locomotor activity in the open field is normal and mice show normal general behaviors such as gait posture

nervous system

abnormal nervous system electrophysiology ( J:257982 )

• dopamine and baclofen both fail to cause currents in single putative dopamine neurons from the ventral tegmental area

• however, glutamic acid causes currents to the same extent as that in VTA neurons from controls