Mouse Genome Informatics
cn1
    Psmc1tm1Maye/Psmc1tm1Maye
Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-cre)1Lin/0

involves: 129 * C57BL/6 * CD-1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• die at 3-4 months of age

growth/size/body
• subtle growth retardation starting 5 weeks of age and becoming statistically significant by 8 weeks

behavior/neurological
• lack interest in locating food at 3-4 months of age
• significantly more anxious in open-field analysis at 6 weeks
• obvious spatial learning deficits in the Morris water maze at 8 weeks

nervous system
• expansion of the ventricular cavities accompanying atrophy of the forebrain
• extensive neuronal loss by 8 weeks
• significant progressive atrophy of the forebrain
• extensive gliosis as a result of the neuronal damage
• numerous eosinophilic intraneuronal paranuclear inclusions, containing ubiquitin, alpha-synuclein, and p62, similar to Lewy bodies
• neurodegeneration was evident in neurons expressing Tg(Camk2a-tTA)1Mmay in forebrain, hippocampus, striatum, and amygdala

cellular


Mouse Genome Informatics
cn2
    Grin1tm1Rsp/Grin1tm1Rsp
Tg(Camk2a-tTA)1Mmay/?
Tg(tetO-cre)LC1Bjd/?

involves: 129S1/Sv * 129X1/SvJ * BALB/c * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• complete loss of NMDAR-mediated long term potential at dentate gyrus synapses
• however, long term potentiation at Schaffer collateral-CA1 synapses is similar to wild-type mice despite residual Cre activity in CA1 pyramidal cells

behavior/neurological
• mice exhibit impaired spatial working memory but normal spatial reference memory in a 3 from 6 radial arm maze task


Mouse Genome Informatics
cn3
    Gabrg2tm2Spet/Gabrg2+
Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-cre)LC1Bjd/0

involves: 129S1/Sv * 129X1/SvJ * BALB/c * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• induced by pentylenetetrazil in mice treated with doxycycline treatment between conception and P21 or not treated with doxycycline at all
• induced by pentylenetetrazil compared with Gabrg2tm2Spet heterozygotes
• doxycycline treatment between conception and P21 increased the time to first clonic seizure compared with mice not treated with doxycycline
• however, no seizure kindling effect is observed

nervous system
• induced by pentylenetetrazil in mice treated with doxycycline treatment between conception and P21 or not treated with doxycycline at all
• induced by pentylenetetrazil compared with Gabrg2tm2Spet heterozygotes
• doxycycline treatment between conception and P21 increased the time to first clonic seizure compared with mice not treated with doxycycline
• however, no seizure kindling effect is observed


Mouse Genome Informatics
cn4
    Npy1rtm1.1Ceva/Npy1rtm1.1Ceva
Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-cre)LC1Bjd/0

involves: 129S1/Sv * 129X1/SvJ * BALB/c * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
adipose tissue
• Background Sensitivity: in doxycycline-treated mice raised by FVB/J
• however, doxycycline-treated mice raised by C57BL/6J dams exhibit normal white adipose tissue weight
• Background Sensitivity: in doxycycline-treated mice raised by FVB/J
• however, doxycycline-treated mice raised by C57BL/6J dams exhibit normal white adipose tissue weight
• Background Sensitivity: visceral, epididymal and subcutaneous white adipose tissue in doxycycline-treated mice raised by FVB/J
• however, doxycycline-treated mice raised by C57BL/6J dams exhibit normal white adipose tissue weight

homeostasis/metabolism
• Background Sensitivity: in doxycycline-treated mice raised by FVB/J
• however, doxycycline-treated mice raised by C57BL/6J dams exhibit normal leptin levels
• Background Sensitivity: in doxycycline-treated mice raised by FVB/J
• however, doxycycline-treated mice raised by C57BL/6J dams exhibit normal leptin levels

behavior/neurological
• Background Sensitivity: in an elevated plus maze and open field test, doxycycline-treated mice raised by FVB/J dams exhibit increased anxiety-related behaviors compared with similarly fostered control mice
• however, doxycycline-treated mice fostered by C57BL/6J dams exhibit normal anxiety
• doxycycline-treated mice raised by C57BL/6J dams exhibit decreased total distance traveled in an open field compared with control mice and doxycycline-treated mice raised by FVB/J dams

growth/size/body
• after doxycycline treatment at P41 and P48, mice raised by FVB/J dams, and to a lesser extent raised by C57BL/6J dams, exhibit slower body weight gain compared with control mice

integument
• Background Sensitivity: in doxycycline-treated mice raised by FVB/J
• however, doxycycline-treated mice raised by C57BL/6J dams exhibit normal white adipose tissue weight


Mouse Genome Informatics
cx5
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-APPSwInd)107Dbo/0

(FVB/NJ x B6.Cg-Tg(tetO-APPSwInd)107Dbo Tg(Camk2a-tTA)1Mmay)F1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
N
• bitransgenic (off-DOX) males perform like wild-type males in Plus water maze apparatus, swimming abilities, and latency to find platform (J:195259)
• in a test of long-term reference memory, radial arm water maze (RAWM) administered after a 24 hour delay, bi-transgenic males (off-DOX) performed at the level of chance with a significantly increased number of errors compared to wild type (J:195259)
• bi-transgenic mice (on-DOX) perform similar to non-transgenic controls in RAWM (J:195259)
• in a test of cognitive flexibility, as assessed by changing the water maze escape platform position daily, bi-transgenic males (on-DOX) continue to visit the original location significantly more frequently than non-transgenic controls, however, in subsequent sessions the error rate becomes similar to non-transgenic controls (J:195259)
• 12.5 month old bi-transgenic males (off-DOX) exhibit significantly less preference for exploring the new arm of the two trial Y maze (a test of short term spatial memory) (J:195259)
• 12.5 month old bi-transgenic males (on-DOX) exhibit a preference for the new arm (J:195259)
• 12.5 month old bi-transgenic males (off-DOX) exhibit improved performance after successive trials, but an increased number of errors compared to wild-type non-Tg and on-DOX Tg controls in the radial arm water maze (RAWM), a test of long term spatial memory (J:195259)

nervous system
• found in the CA layer of the hippocampus in off-DOX and on-DOX (for 7 days) 23 month old bi-transgenic males, however, after 5 weeks on doxycycline APP/amyloid beta (as assessed by mAb 6E10) immunoreactivity disappears (J:195259)
• a low level of mobile, water-extractable Abeta42 is present in bitransgenic males treated with DOX for up to 4 weeks (J:195259)

homeostasis/metabolism
• found in the CA layer of the hippocampus in off-DOX and on-DOX (for 7 days) 23 month old bi-transgenic males, however, after 5 weeks on doxycycline APP/amyloid beta (as assessed by mAb 6E10) immunoreactivity disappears (J:195259)
• a low level of mobile, water-extractable Abeta42 is present in bitransgenic males treated with DOX for up to 4 weeks (J:195259)


Mouse Genome Informatics
cx6
    Apba2tm1Tsuz/Apba2tm1Tsuz
Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-APBA2,-lacZ)1Ito/0

B6.Cg-Apba2tm1Tsuz Tg(Camk2a-tTA)1Mmay Tg(tetO-APBA2,-lacZ)1Ito
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• with or without DOX administration, adult mice bury significantly more marbles than null mice in the marble burying test
• DOX administration to parental mice results in progeny which bury significantly fewer marbles than wild-type mice in the marble burying test
• without DOX administration mice displace significantly more food pellets from a tube than null mice in a burrowing test
• with or without DOX administration mice have decreased locomotor activity
• without DOX administration total number of resident social interactions with intruder mice are significantly increased compared to null mice in a resident-intruder test


Mouse Genome Informatics
cx7
    Tg(Camk2a-tTA)1Mmay/?
Tg(tetO-CALY)5Cber/?

B6.Cg-Tg(Camk2a-tTA)1Mmay Tg(tetO-CALY)5Cber
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• greater distance traveled and more exploration of the center in an open field test
• increased time spent in the open box in a light/dark box apparatus
• enter the open arm of an elevated plus maze more frequently than controls and travel greater distances in the apparatus


Mouse Genome Informatics
cx8
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-Gnas)1593Mpke/0

B6.Cg-Tg(Camk2a-tTA)1Mmay Tg(tetO-Gnas)1593Mpke
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• in mice never fed doxycycline or fed doxycycline only during development or only during adulthood
• mice never fed doxycycline or fed doxycycline only during development or only during adulthood exhibit a decrease in dorsal striatum compared with wild-type mice
• mice never fed doxycycline or fed doxycycline only during development or only during adulthood exhibit a decrease in ventral striatum compared with wild-type mice
• in mice never fed doxycycline but not mice fed doxycycline during adulthood only
• mice that never received doxycycline exhibit decreased prepulse inhibition compared with wild-type mice
• however, mice that receive doxycycline throughout development or only in adulthood or are treated with haloperidol exhibit normal prepulse inhibition
• in mice never fed doxycycline but not mice fed doxycycline during adulthood only

behavior/neurological
N
• mice exhibit no change in anxiety-related behavior (J:166114)
• mice never fed doxycycline exhibit impaired short-term and long-term memory for hippocampus-dependent contextual fear compared with wild-type mice
• mice fed doxycycline only during adulthood or only during the retrieval but not training exhibit reduced levels of contextual fear 24 hours following training compared with wild-type mice
• however, mice fed doxycycline only during development or only after training through retrieval exhibit normal long-term memory for contextual fear
• mice never fed doxycycline or only fed doxycycline during development but not during adulthood only exhibit impaired spatial learning in a Morris water maze compared with wild-type mice
• mice never fed doxycycline or only fed doxycycline during development or during adulthood only exhibit impaired spatial memory in a Morris water maze compared with wild-type mice
• in mice never fed doxycycline or only fed doxycycline during adulthood but not during development only

Mouse Models of Human Disease
OMIM IDRef(s)
Schizophrenia; SCZD 181500 J:166114


Mouse Genome Informatics
cx9
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-Csnk1d)#Mfla/0

involves: 129/Sv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
N
• mice exhibit normal social and circadian behaviors (J:158611)
• mice exhibit a 40 minute delay in D-amphetamine-induced hyperlocomotion compared with similarly treated wild-type mice
• D-amphetamine-treated mice exhibit a dose dependent suppression of vertical activity unlike similarly treated wild-type mice that exhibit an increase in vertical activity
• in a dark-light choice test, mice exhibit increased rearing in the light compartment compared with wild-type mice
• in an elevated place maze, mice spend more time in the open arms than wild-type mice
• in a novelty suppressed feeding paradigm, mice exhibit shorter latency to feeding compared with wild-type mice
• however, mice exhibit normal anxiety-related behavior in an open field, forced swim, and tail suspension tests
• mice exhibit a 40 minute delay in D-amphetamine-induced hyperlocomotion compared with similarly treated wild-type mice
• D-amphetamine-treated mice exhibit a dose dependent suppression of vertical activity unlike similarly treated wild-type mice that exhibit an increase in vertical activity
• in an open field test, mice exhibit increased vertical activity compared with wild-type mice
• increased activity begins at 6 weeks of age and persists at least until 16 months of age
• however, treatment with methylphenidate or haloperidol suppresses vertical activity
• in an open field test, mice exhibit increased horizontal and vertical activity compared with wild-type mice
• increased activity begins at 6 weeks of age and persists at least until 16 months of age
• however, treatment with methylphenidate or haloperidol decreases activity levels
• in an open field box, mice fail to build a nest unlike wild-type mice

nervous system
• protein expression of dopamine receptors 1 and 2 and NMDA receptors are decreased in the striatum compared to in wild-type mice

homeostasis/metabolism
• MK801-treated mice exhibit a more rapid onset of increased horizontal activity and decreased vertical activity compared with similarly treated wild-type mice

Mouse Models of Human Disease
OMIM IDRef(s)
Attention Deficit-Hyperactivity Disorder; ADHD 143465 J:158611


Mouse Genome Informatics
cx10
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-MAPT*P301L)#Kha/0

involves: 129/Sv * C57BL/6 * CBA * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• progressive atrophy of dentate granule cells
• progressive atrophy of hippocampal pyramidal neurons


Mouse Genome Informatics
cx11
    Tg(Camk2a-tTA)1Mmay/?
Tg(tetO-MAPT*P301L)#Kha/?

involves: 129S6/SvEvTac * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• a significant loss in brain weight by 5.5 months
• when treated with doxycycline during 5.5 to 10 months, the loss of brain weight was significantly protected
• significant decrease in total numbers of CA1 hippocampal neurons
• CA1 neuron estimates were stabilized after brief (6- to 8-week) doxycycline treatment
• gross atrophy of the forebrain was evident in a 10-month-old mouse
• develop argyrophilic tangle-like inclusions in the cortex by 4 months and in the hippocampal formation by 5.5 months
• when treated with doxycycline at 2.5 month, the tau pathology ceased to progress
• the neuronal inclusions composed of a mass of straight tau filaments
• when treated with doxycycline at 2.5 month, the tau pathology ceased to progress
• approximately 23% of CA1 pyramidal cells remaining at 8.5 months
• CA1 neuron estimates were stabilized after brief (6- to 8-week) doxycycline treatment

behavior/neurological
• he retention of spatial memory examined by the Morris water maze were impaired as the mice aged
• deficit in spatial navigation was also seen in younger mice
• the performance improved when treated with doxycycline at 2.5 month-old or at 5.5 month-old

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:99626


Mouse Genome Informatics
cx12
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-MAPT*P301L)#Kha/0

involves: 129S6/SvEvTac * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• amount of time spent in open arms of elevated plus maze is increased relative to nontransgenic mice at 6 and 10 months of age, but not 2 months
• higher ratio of time spent in open not closed arms relative to nontransgenic mice at 10 months of age, but not 2 or 6 months
• exploration of light chamber is increased relative to nontransgenic mice at 6 months of age, but not 2 or 10 months
• higher ratio of time spent in light not dark relative to nontransgenic miceat 10 months of age, but not 2 or 6 months
• decreased tendency to explore the center of the open field relative to nontransgenic mice
• progressive decrease in percent of time spent freezing in response to unconditioned stimulus beginning at 2 months of age
• progressive decrease in percent of time spent freezing in response to conditioned stimulus beginning at 6 months of age
• mice exhibit progressive hyperactivity in open field analysis and elevated plus maze
• total distance travelled in open field assay is increased relative to nontransgenic mice at 6 and 10 months of age, but not 2 months
• average speed is increased relative to nontransgenic mice at 6 and 10 months of age, but not 2 months
• total time spent immobile is increased relative to nontransgenic mice at 6 and 10 months of age, but not 2 months

nervous system
• neurofibrilliary tangles are observed by immunostaining in the CA1 region of the hippocampus beginning at 6 months of age and progressing to an extensive pathology by 11 months of age
• neurofibrilliary tangles are observed by immunostaining in the amygdala beginning at 2 months of age and progressing to an extensive pathology by 10 months of age
• tau burden increases with age in the amygdala and CA1 region of the hippocampus

Mouse Models of Human Disease
OMIM IDRef(s)
Frontotemporal Dementia; FTD 600274 J:207366


Mouse Genome Informatics
cx13
    Lrrk2tm1.1Cai/Lrrk2+
Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-SNCA*A53T)E2Cai/0

involves: 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• somatic alpha synuclein in neurons is apparent at 12 months
• increased microglial activation is observed in the brain at 12 months
• numbers of residual neurons is significantly lower than non transgenic controls
• significant at 12 months
• the Golgi complex shows severe fragmentation in 12 month old animals
• neurodegeneration significant at 12 months

immune system
• increased microglial activation is observed in the brain at 12 months

hematopoietic system
• increased microglial activation is observed in the brain at 12 months


Mouse Genome Informatics
cx14
    Lrrk2tm1.1Cai/Lrrk2tm1.1Cai
Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-SNCA*A53T)E2Cai/0

involves: 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
N
• no apparent neurodegeneration is observed in 12-month old mice; no significant elevation of astrocytosis, microgliosis or somatic accumulation of alpha-synuclein is detected in striatum at 12 months (J:156512)


Mouse Genome Informatics
cx15
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-SNCA)7Vle/0

involves: C3H/HeH * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• atrophy of hippocampal dentate gyrus neurons is seen by P21
• mutants fed a doxycycline diet to suppress transgene expression from E0.5 until P21 and then switched to a regular diet to induce expression show accumulation of alpha-synuclein within neurons of the septum, cingulated cortex, subthalamic nucleus, mammillary body, and brainstem, but not hippocampus at 8 months of age

behavior/neurological
N
• mutants do not exhibit impaired contextual fear memory at 8 months of age (J:174555)


Mouse Genome Informatics
cx16
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-SNCA*A53T)33Vle/0

involves: C3H/HeH * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• dentate gyrus neuron loss is due to cell death not decreased cell proliferation
• mild hippocampal dentate gyrus neuron atrophy is seen at P14, and is striking by P21 (J:156801)
• mice treated with doxycycline to suppress alpha-synuclein expression, do not exhibit neuron atrophy (J:156801)
• mutants fed a doxycycline diet to suppress transgene expression from E0.5 until P21 and then switched to a regular diet to induce transgene expression exhibit severe loss of dentate gyrus granule cells (J:174555)
• mutants fed a doxycycline diet to suppress transgene expression from E0.5 until P21 and then switched to a regular diet to induce transgene expression exhibit severe loss of hippocampal pyramidal cells
• mutants fed a doxycycline diet to suppress transgene expression from E0.5 until P21 and then switched to a regular diet to induce transgene expression exhibit severe reduction in cortex thickness
• gliosis in the hippocampus, near the dentate gyrus
• mutants fed a doxycycline diet to suppress transgene expression from E0.5 until P21 and then switched to a regular diet to induce transgene expression exhibit progressive reactive astrogliosis; mutants further treated with doxycycline at 9 months, show prevention of further reactive gliosis
• mutants fed a doxycycline diet to suppress transgene expression from E0.5 until P21 and then switched to a regular diet to induce transgene expression exhibit a reduction in presynaptic vesicle proteins indicating a disruption in synaptic vesicles in the mossy fiber terminals
• mutants fed a doxycycline diet to suppress transgene expression from E0.5 until P21 and then switched to a regular diet to induce expression exhibit abnormal accumulation of alpha-synuclein in limbic areas including the cingulated cortex, the hippocampus, dentate gyrus, and mammillary body, as well as the olfactory bulb, septum and subthalamic nucleus, by 4 months of age; superior colliculus, ventral tegmental area, brainstem, and spinal cord also shows a limited amount of alpha-synuclein accumulation
• young mice (4-12 months) fed a doxycycline diet to suppress transgene expression from E0.5 until P21 and then switched to a regular diet to induce expression exhibit early, soluble, neuritic, and synaptic accumulations, which over time progress to become insoluble cytoplasmic inclusions at 20 months
• mice treated with doxycyline starting at 9 months for 3 months and analyzed at 12 months do not exhibit abnormal alpha-synuclein accumulations in the hippocampus or dentate gyrus; doxycycline however did not clear alpha-synuclein pathology in the mammillary bodies, olfactory bulb or septum, but did arrest further accumulation progression
• neuronal loss in the cortex and hippocampus is seen in 20-22 old mutants fed a doxycycline diet to suppress transgene expression from E0.5 until P21 and then switched to a regular diet to induce transgene expression
• postmitotic hippocampal dentate gyrus neuron degeneration is seen by P14, but no degeneration of proliferating cells

behavior/neurological
• mutants fed a doxycycline diet to suppress transgene expression from E0.5 until P21 and then switched to a regular diet to induce transgene expression exhibit impaired contextual fear memory at 8 months of age; mutants further treated with doxycycline at 9 months show improved memory function
• normal chow-fed mutants at 12 months of age show impaired contextual fear memory

cellular
• dentate gyrus neuron loss is due to cell death not decreased cell proliferation

Mouse Models of Human Disease
OMIM IDRef(s)
Dementia, Lewy Body; DLB 127750 J:174555


Mouse Genome Informatics
cx17
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-APPSwInd)885Dbo/0
Tg(tetO-LRRK2*G2019S)E3Cai/0

involves: C3H/HeJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• no acceleration of degeneration is observed compared to Tg(Camk2a-tTA)1Mmay/Tg(tetO-LRRK2*G2019S)E3Cai mice (G2019S)


Mouse Genome Informatics
cx18
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-APPSwInd)885Dbo/0

involves: C3H/HeJ * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• mice exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus
• mice exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus
• however, when mice are reared on doxycycline, cell loss is not observed
• mice produce transgenic APP protein at 10- to 30-fold over endogenous App levels
• expression of APPSw/Ind is higher relative to other three double transgenic lines, and suprression requires more doxycycline than the other three lines

homeostasis/metabolism


Mouse Genome Informatics
cx19
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-APPSwInd)107Dbo/0

involves: C3H/HeJ * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• doxycycline-mediated suppression of transgenic APPSwInd synthesis leads to parallel reductions of amyloid beta peptide levels
• early onset amyloid formation is observed, with plaques observed as early as 8 weeks of age in mice receiving no doxycycline (DOX) treatment
• plaques are restricted to the forebrain, including the cortex, hippocampus, olfactory bulb, and striatum; by 6 months, amyloid burden covers large cortical and hippocampal areas
• first observed plaques are fibrillar-core deposits; in 6 month old animals, diffuse plaques are apparent and these are abundant at 9 months, while in 9-12 month-old mice, plaques are visible in the thalamus
• no lesions are observed in the cerebellum or brain stem
• animals receiving no treatment display moderate amyloid pathology at 6 months, which progresses to a severe amyloid burden by 9 months
• mice raised for 6 months with no (DOX) treatment, followed by 3 or 6 months of DOX treatment show similar pathology to untreated 6-month old animals, despite relatively long lesion clearance times
• mice exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus
• mice exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus
• however, when mice are reared on doxycycline, cell loss is not observed
• first visible plaques are fibrillary-cored deposits
• activated astrocytes are found near plaques in all affected mice glial pathology is more severe in older mice
• if transgene expression is suppressed with doxycycline treatment, pathology does not progress in severity
• mice produce transgenic APP protein at 10- to 30-fold over endogenous App levels
• sensitivity of transgene suppression by doxycycline is intermediate between mice of line 885 and line 102
• neuritic pathology is observed around plaques; neuritic pathology is more severe in older mice
• if transgene expression is suppressed with doxycycline treatment, pathology does not progress in severity

behavior/neurological
• all animals raised with doxycycline have altered circadian rhythms with less distinction between day- and nighttime activity levels
• hyperactive behavior is partially reversed in some mice by 1 month of transgene suppression starting at 4-5 months of age
• untreated mice show hyperactivity, often running in circles around the perimeter of cages
• similar patterns of activity are observed in Morris water maze, with repetitive swim patterns seen in radial water maze swim test
• hyperactive phenotype penetrance is ~100%
• untreated mice show 10-fold more ambulatory activity during the dark phase; even in light phase, activity is several-fold increased compared to wild-type controls; this activity is completely abolished in mice raised on doxycycline

immune system
• neuritic pathology is observed around plaques; neuritic pathology is more severe in older mice
• if transgene expression is suppressed with doxycycline treatment, pathology does not progress in severity

homeostasis/metabolism
• doxycycline-mediated suppression of transgenic APPSwInd synthesis leads to parallel reductions of amyloid beta peptide levels
• early onset amyloid formation is observed, with plaques observed as early as 8 weeks of age in mice receiving no doxycycline (DOX) treatment
• plaques are restricted to the forebrain, including the cortex, hippocampus, olfactory bulb, and striatum; by 6 months, amyloid burden covers large cortical and hippocampal areas
• first observed plaques are fibrillar-core deposits; in 6 month old animals, diffuse plaques are apparent and these are abundant at 9 months, while in 9-12 month-old mice, plaques are visible in the thalamus
• no lesions are observed in the cerebellum or brain stem
• animals receiving no treatment display moderate amyloid pathology at 6 months, which progresses to a severe amyloid burden by 9 months
• mice raised for 6 months with no (DOX) treatment, followed by 3 or 6 months of DOX treatment show similar pathology to untreated 6-month old animals, despite relatively long lesion clearance times

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:109829


Mouse Genome Informatics
cx20
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-APPSwInd)18Dbo/0

involves: C3H/HeJ * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• amyloid burden worsens in untreated animals between 6 and 9 months of age
• with 3 months of doxycyclin treatment beginning at 6 months of age, suppression of transgene synthesis and complete arrest of increase in amyloid pathology is observed compared to untreated mice; however, in these mice no sign of reduction in amyloid burden is observed
• mice produce transgenic APP protein at 10- to 30-fold over endogenous App levels
• sensitivity of transgene suppression by doxycycline is intermediate between mice of line 885 and line 102

homeostasis/metabolism
• amyloid burden worsens in untreated animals between 6 and 9 months of age
• with 3 months of doxycyclin treatment beginning at 6 months of age, suppression of transgene synthesis and complete arrest of increase in amyloid pathology is observed compared to untreated mice; however, in these mice no sign of reduction in amyloid burden is observed

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:109829


Mouse Genome Informatics
cx21
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-APPSwInd)102Dbo/0

involves: C3H/HeJ * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• mice produce transgenic APP protein at 10- to 30-fold over endogenous App levels
• suppression of transgene expression in these mice is most sensitive to doxycycline of the four lines tested

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:109829


Mouse Genome Informatics
cx22
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-TARDBP)12Vle/0

involves: C3H/HeJ * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• microglial activation is seen in the cortex and hippocampus as early as 1 month after Dox removal
• 6 months following Dox removal
• 20% loss of dentate gyrus neurons at 1 month and about 75% loss by 3 months after Dox removal
• astrocytic activation is seen in the cortex and hippocampus as early as 1 month after Dox removal
• mutants switched to a doxycycline (Dox)-free diet at 28 days of age show progressive neurodegeneration, with neuron loss in the hippocampal dentate gyrus and neocortex beginning at about 1 month after Dox removal

behavior/neurological
• variable clasping behavior is seen approximately 1-3 months after Dox removal

hematopoietic system
• microglial activation is seen in the cortex and hippocampus as early as 1 month after Dox removal

immune system
• microglial activation is seen in the cortex and hippocampus as early as 1 month after Dox removal


Mouse Genome Informatics
cx23
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-TARDBP*)4Vle/0

involves: C3H/HeJ * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• about 50% loss of dentate gyrus neurons at 1 month after Dox removal
• massive gliosis in cortical and hippocampal regions following Dox removal
• gliosis in the corticospinal tract, including the striatum, cerebral peduncles, medullary pyramids, and cervical spinal cord, following Dox removal
• selective loss of corticospinal tract axons in cervical spinal cord associated with gliosis following Dox removal
• however, lower motor neuron loss is not observed
• mutants rarely show accumulation of hyperphosphorylated, ubiquitinated cytoplasmic aggregates of TARDBP in neurons following Dox removal (around 1% of neurons showing aggregates)
• mutants switched to a doxycycline (dox)-free diet at 28 days of age show progressive neurodegeneration; neuron loss is particularly evident in the deep neocortical layers and in the dentate gyrus but is rarely seen in the hippocampal CA1 subfield and the olfactory bulb
• selective loss of corticospinal tract axons in cervical spinal cord following Dox removal

behavior/neurological
• abnormal limb clasping as early as 1 week after dox removal that continues throughout life until sacrifice


Mouse Genome Informatics
cx24
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-COX8A/EYFP)1Ksn/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
normal phenotype
• mice appear normal and healthy, and expression of EYFP is detected in neuronal mitochondria under appropriate conditions


Mouse Genome Informatics
cx25
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-S100a10)1Pggd/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• mice exhibit decreased depression-related behavior such as immobility when suspended by their tails
• however, treatment with doxycycline restores normal depression-related behaviors
• mice exhibit decreased thigmotaxis and increased horizontal activity in an open-field test
• however, treatment with doxycycline restores normal anxiety-related behaviors


Mouse Genome Informatics
cx26
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2)C77Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
N
• no neuronal degeneration is observed at 1 month in the striatum or cortex of LRRK2WT-L mice (J:156512)


Mouse Genome Informatics
cx27
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2)C77Cai/0
Tg(tetO-SNCA*A53T)E2Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• increasing accumulation of alpha-synuclein is detected in cell bodies in brains of A53T/LRRK2WT-L at 1 month compared to LRRK2WT-L animals
• increased microglial activation is observed in the brain
• A53T/LRRK2WT-L mice show significant elevation of GFAP-positive astrocytes in the striatum compared to A53T mice
• neurodegeneration is accelerated in the striatum
• increasing accumulation of alpha-synuclein is detected in cell bodies at 1 month

behavior/neurological
• mice show no apparent motor phenotype up to 6 months of age

hematopoietic system
• increased microglial activation is observed in the brain

immune system
• increased microglial activation is observed in the brain


Mouse Genome Informatics
cx28
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2*)D10Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• increased framentation of the Golgi complex is observed in KD mice


Mouse Genome Informatics
cx29
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2*)D10Cai/0
Tg(tetO-SNCA*A53T)E2Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• increasing accumulation of alpha-synuclein is detected in cell bodies at 1 month in A53T/KD mice compared to KD animals
• increased framentation of the Golgi complex is observed
• neuropathology is accelerated in A53T/KD mice compared to A53T mice


Mouse Genome Informatics
cx30
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2*G2019S)E3Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size/body
• starting at 1 year, mice appear to gain less body weight than non-transgenic and Tg(tetO-LRRK2*G2019S)E3Cai single mutant mice, but are not different from Tg(Camk2a-tTA)1Mmay animals

behavior/neurological
N
• mice show normal performance in the rotarod test (J:156512)
• mice show significantly increased ambulatory activities starting at 12 months of age; at 12 months mice show a trend to increased rearing activities but this does not reach statistical significance

nervous system
N
• no significant changes in neuron counts are observed compared to non-transgenic controls at the frontal cortex or dorsal striatum in 6- or 20-month old mice (J:156512)
• no increase in reactive astrocytosis or microglial activation are detected in the striatum or cortex at 20 months (J:156512)
• no alpha-synuclein accumulation is observed in neurons at 20 months (J:156512)
• the Golgi complex is drastically altered in neurons at 1 month, appearing thinner and fragmented
• at 6 months fragmentation of the cis-Golgi apparatus is similar to that in LRRK2WT and A53T/LRRK2 neurons
• at 1 month, the medial/trans-Golgi in neurons is significantly altered
• brain homogenates moderately elevated levels of ubiquitinated proteins at 18 months compared to non-transgenic controls


Mouse Genome Informatics
cx31
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2*G2019S)E3Cai/0
Tg(tetO-SNCA*A53T)E2Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• substantial accumulation of alpha-synuclein is detected in cell bodies at 1 month
• exacerbated in the striatum compared to A53T mice at 1 month of age
• levels of microglial activation are higher than in A53T/LRRK2WT mice
• exacerbated in the striatum compared to A53T mice at 1 month of age
• levels of GFAP-positive cells are higher than in A53T/LRRK2WT mice
• the Golgi complex is drastically altered in neurons at 1 month with severely fragmented
• at 1 month, the medial/trans-Golgi in neurons is severely fragmented
• a significant increase in detergent-insoluble high molecular weight (HMW) alpha synuclein is detected in 1 month old mice compared to A53T age-matched mice
• exacerbated in the striatum compared to A53T mice at 1 month of age
• dramatic loss (>85%) of striatal neurons is seen in the dorsal striatum

hematopoietic system
• exacerbated in the striatum compared to A53T mice at 1 month of age
• levels of microglial activation are higher than in A53T/LRRK2WT mice

immune system
• exacerbated in the striatum compared to A53T mice at 1 month of age
• levels of microglial activation are higher than in A53T/LRRK2WT mice

cellular
• in striatal neurons at 1 month, numerous mitochondria have denser matrices and widened cristae compared to controls or A53T mice (seen with 3.5x greater frequency than in A53T mice); these mitochondria are not functional


Mouse Genome Informatics
cx32
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2)C7874Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
N
• no gross neuropathological phenotypes are observed in 12-month old animals (J:156512)
• no significant changes in neuron counts are observed compared to non-transgenic controls at the frontal cortex or dorsal striatum in 6- or 20-month old mice (J:156512)
• the Golgi complex is drastically altered in neurons at 1 month, appearing thinner and fragmented
• at 6 months fragmentation of the cis-Golgi apparatus is similar to that in LRRK2WT and A53T/LRRK2 neurons
• at 1 month, the medial/trans-Golgi in neurons is significantly altered with ratio of fragmented trans-Golgi significantly increased compared to non-transgenic animals


Mouse Genome Informatics
cx33
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2)C7874Cai/0
Tg(tetO-SNCA*A53T)E2Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• increasing accumulation of alpha-synuclein is detected in cell bodies at 1 month compared to A53T/LRRK2WT-L animals
• increased microglial activation is observed in the brain
• neuron loss is detected at 6 months and later
• A53T/LRRK2WT mice show significant elevation of GFAP-positive astrocytes in the striatum compared to A53T mice
• more GFAP-positive astrocytes are found in the brain than in A53T/LRRK2WT-L brains
• the Golgi complex is drastically altered in neurons at 1 month with severely fragmented cis-Golgi
• at 1 month, the medial/trans-Golgi in neurons is severely fragmented
• neurodegeneration is accelerated in the striatum
• dramatic loss (>80%) of striatal neurons is seen in the dorsal striatum
• most degenerating neurons are striatal medium-sized spiny neurons (MSN)
• neuropathology is accelerated in mice compared to A53T mice
• in 6 month old mice, elevated levels of ubiquitin are detected in somas and nuclei of cortical neurons; levels of alpha-synuclein and ubiquitin are slightly higher than in A53T mutant mice
• brain homogenates contain significantly elevated levels of ubiquitinated proteins at 3 months

immune system
• increased microglial activation is observed in the brain

hematopoietic system
• increased microglial activation is observed in the brain


Mouse Genome Informatics
cx34
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-SNCA*A53T)E2Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size/body
• A53T mice weigh significantly less than non transgenic mice and Tg(tetO-SNCA*A53T)E2Cai or Tg(Camk2a-tTA)1Mmay single mutants starting at 4 months of age

behavior/neurological
• mice display elevated rearing activities at 6 months of age
• at 2 months of age, mice show drastically increased ambulatory activity

nervous system
• only a few neurons in the brain display alpha-synuclein staining in the cell body at 3 months; somatic accumulation becomes more prominent at 20 months; whereas no accumulation is detected in cell bodies at 1 month
• significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression
• significant at 12 months
• significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression
• neuron loss is detected at 6 months and later
• significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression
• neuron loss is detected at 6 months and later
• in 6 month old mice but not in nontransgenic controls, elevated levels of ubiquitin are detected in somas and nuclei of cortical neurons, but
• significant at 12 months
• significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression
• the Golgi complex is drastically altered in neurons at 1 month, appearing thinner and fragmented
• significant increase in Golgi fragmentation is observed at 6 months
• at 1 month, the medial/trans-Golgi in neurons is significantly altered with ratio of fragmented trans-Golgi significantly increased compared to non-transgenic animals
• significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression
• a significant increase in detergent-insoluble high molecular weight (HMW) alpha synuclein is detected in 12 month old mice compared to 1 month old mice
• significant decrease in HMW alpha-synuclein in total brain homogenates is observed when animals are treated with doxycycline to inhibit transgene expression
• widespread degeneration is observed at 20 months
• age-dependent, progressive neurodegeneration occurs
• neuronal loss is detected in the frontal cortex (>80%) and dorsal striatum (>74%) at 20 months
• a significant reduction (>30%) of striatal neurons is seen at 6 months
• while 3-month old A53T mice show no abnormal neuropathology, but neuropathology is evident at 12 and 20 months
• in 6 month old mice, elevated levels of ubiquitin are detected in somas and nuclei of cortical neurons; at 20 monts, a punctate staining pattern at neuronal processes is observed
• brain homogenates contain significantly elevated levels of ubiquitinated proteins at 3 months

hematopoietic system
• significant at 12 months
• significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression

immune system
• significant at 12 months
• significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression

cellular
• in striatal neurons at 1 month, numerous mitochondria have denser matrices and widened cristae compared to non-transgenic controls; these mitochondria are not functional


Mouse Genome Informatics
cx35
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2*G2019S)E3Cai/0
Tg(tetO-SNCA)1Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• somatic alpha synuclein in neurons is apparent at 1 month


Mouse Genome Informatics
cx36
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-SNCA)1Cai/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
N
• no alpha-synuclein accumulation is observed in neurons at 1 month (J:156512)


Mouse Genome Informatics
cx37
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-SNCA)0Olri/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• in the accelerated rotarod, mutants do not show short-term improvement between trial 1 and trial 2 as in controls, indicating impaired motor skill learning
• 52 week old mutants show impaired memory retention in the Morris water maze when tested 7 days later for their platform preference
• progressive impairment of motor performance that begins around 30 weeks of age
• mice show impaired performance on the rotarod as early as 18 weeks of age, however progressive decline does not start before 30 weeks of age
• progressive motor decline is not reversed by treatment with doxycycline but it does halt further decline

nervous system
• mice show a 49% reduction of newly differentiated neurons in the granular cell layer of the dentate gyrus, and a reduction of DCX-positive neuroblasts, indicating impaired neurogenesis
• doxycycline treatment to inhibit transgene expression starting at 16 weeks of age does not result in reduced neurogenesis
• total number of neuroblasts is reduced in the hippocampus
• reduction of dopamine level in the olfactory bulb in aged mice
• dark cells in the substantia nigra and axonal pathology with condensed mitochondria and lipid droplets indicating degeneration of nigral cells
• large lipid-like drops are seen between nerve fibers of the pars reticulata
• dark degenerated pyramidal cells are scattered between unaffected neurons
• reduction of dopaminergic neurons in the substantia nigra; degenerating cells are most prominent in the pars reticulata
• reduction of dopamine trasnporter binding sites at presynaptic terminals
• degenerated neurons are seen in the hippocampus and substantia nigra, with darkened nuclear and cytoplasmic appearance, slightly collapsed nuclear envelope, and increased accumulation of lysosomes
• proximal dendrites of the CA3 neurons show signs of degeneration
• dark cell degeneration in the CA1 pyramidal cells as well as in interneurons and granule cells of the dentate gyrus
• many alpha-synuclein positive mossy fiber terminals, which may show swollen vesicles and enlarged mitochondria, form asymmetric contracts with immunonegative dendritic spines
• alpha-synuclein accumulates in the stratum lacunosum moleculare and in mossy fibers and their terminals

cellular
• mice show a 49% reduction of newly differentiated neurons in the granular cell layer of the dentate gyrus, and a reduction of DCX-positive neuroblasts, indicating impaired neurogenesis
• doxycycline treatment to inhibit transgene expression starting at 16 weeks of age does not result in reduced neurogenesis
• total number of neuroblasts is reduced in the hippocampus

homeostasis/metabolism
• reduction of dopamine level in the olfactory bulb in aged mice

Mouse Models of Human Disease
OMIM IDRef(s)
Parkinson Disease, Late-Onset; PD 168600 J:132774


Mouse Genome Informatics
cx38
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-MAPT*K280,-luc)#Eman/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• tau tangles are seen as early as 2-3 months after doxycycline removal (at 6 weeks after birth to induce gene expression) in the entorhinal cortex and amygdala (J:131379)
• by 15 months after doxycycline removal, neurofibrillary tangles are seen in the neocortex (J:131379)
• neurofibrillary tangles persist in mice that are doxycycline treated for 4 months after 10 months of transgene expression (J:131379)
• tau aggregates are seen in the cortex as early as 2-3 months after doxycycline removal (at 6 weeks after birth to induce gene expression) (J:131379)
• tau aggregates include both endogenous and the exogenous tau protein (J:131379)
• when expression is switched off by addition of doxycycline, soluble and aggregated exogenous tau disappears within 1.5 months, however tangles of mouse tau remain (J:131379)
• tau aggregates are seen at 10 months after doxycycline removal to switch on expression (J:131379)
• moderate reduction in tau aggregates is seen in mice that express the transgene for 10 months and then are switched off with doxycycline treatment for 4 months (J:131379)
• exogenous tau disappears from tau aggregates in mice that express the transgene for 10 months and then are switched off with doxycycline treatment for 4 months (J:131379)
• missorting of tau into the somatodendritic compartment of cortical and hippocampal neurons is seen after doxycycline removal (J:131379)
• astrogliosis is seen in the hilus region 21 months after doxycycline removal (J:131379)
• activated astrocytes are detected inside the dentate gyrus after doxycycline removal, indicating inflammatory processes (J:169532)
• by 15 months after doxycycline removal, dystrophic neurites are seen
• loss of spine synapses and a decrease in presynaptic proteins in the hippocampus is seen after 9.5 months without doxycycline (J:131379)
• synapses decrease by about 30% after 10 months of expression (doxycycline removal) but only by about 15% when expression is then switched off with doxycycline treatment for 4 months, indicating some recovery of synapses (J:131379)
• some neurons that lack neurofibrillary tangles exhibit incipient degeneration as early as 2-3 months after doxycycline removal (J:131379)
• neuronal loss is seen in the granule cells of the dentate gyrus starting at 5 months after doxycycline removal and is increased at 24 months of gene expression such that shrinkage of the molecular layer is observed (J:131379)
• when expression is switched off again by addition of doxycycline for 1.5 months, the hippocampal pyramidal areas that retain neurofibrillary tangles display neuronal loss (J:131379)
• neuronal loss is seen at 10 months after doxycycline removal in different regions of the hippocampus and cortex (J:169532)
• neuronal loss is seen in the CA1 and dentate gyrus region of the hippocampus in mice that express the transgene for 10 months and then are switched off with doxycycline treatment for 4 months (J:169532)
• mice at 10 months after doxycycline removal show reduced short term plasticity at the mossy fiber-CA3 synapse
• impairment of synaptic facilitation in mice at 10 months after doxycycline removal; this impairment is reversible after expression of the transgene is switched off with doxycycline treatment for 4 months
• mice at 10 months after doxycycline removal show reduced frequency facilitation induced by continuous stimulation at 1 Hz for 1 min; switching off transgene expression with doxycycline for 4 months partially restores the initial rising phase of frequency facilitation
• LTP is impaired in CA3 and CA1 areas of the hippocampus in mice at 10 months after doxycycline removal; LTP is recovered after expression of the transgene is switched off with doxycycline treatment for 4 months
• posttetanic potentiation (PTP) is reduced in CA3 areas of the hippocampus in mice at 10 months after doxycycline removal; PTP is recovered after expression of the transgene is switched off with doxycycline treatment for 4 months

behavior/neurological
• mice at 10 months after doxycycline removal exhibit impaired memory in the passive avoidance test, reentering the dark compartment where mild footshock was introduced faster than controls which avoid the compartment
• in the Morris water maze task, mice 10 months after doxycycline removal show a slower rate of learning to find the submerged escape platform, especially at days 2 and 3 of training
• however, mice show normal behavior in the probe trial after the acquisition phase
• in reversal learning during which the platform is transferred to another quadrant, mice at 14 months after doxycycline removal are slower to reach the platform on days 2 and 3 compared to wild-type mice or mutant mice in which expression was turned off with doxycycline treatment for 4 months, and they spend more time searching the former target quadrant than the quadrant where the platform is now located
• lower rotarod performance at 10 months after doxycycline removal to induce expression, showing a lower performance on the first two trial but normal performance in the last trial
• however, grip strength and performance in spontaneous home cage activity is normal at 10 months after doxycycline removal

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:131379 , J:169532


Mouse Genome Informatics
cx39
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-MAPT*K280*I277P*I308P,-luc)#Eman/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
N
• tau aggregates, neurofibrillary tangles, and neuron degeneration are not seen even after 22 months after doxycycline removal to induce gene expression (J:131379)
(J:169532)
• decrease in synaptic facilitation in mice at 10 months after doxycycline removal which is reversed upon doxycycline treatment to switch off expression
• mice at 10 months after doxycycline removal show reduced extent of frequency facilitation
• posttetanic potentiation (PTP) is reduced in CA3 areas of the hippocampus in mice at 10 months after doxycycline removal, however LTP is normal
• paired-pulse facilitation (PPF) is altered at the 10 and 20 ms interval in CA1 region of the hippocampus


Mouse Genome Informatics
cx40
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-HTT*94Q,-lacZ)1Rhn/0

involves: C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• some mice die between 8 to 10 months due to injuries sustain from fighting with other mice
• fewer than expected mice are recovered due to prenatal lethality
• however, treatment of pregnant dams with doxycycline eliminates prenatal lethality

nervous system
• ventricles are enlarged compared to in wild-type mice
• the striatum is reduced in size compared to in wild-type mice
• the ventricular zone of the striatum is narrower than in wild-type mice
• the area of the caudate putamen is reduced compared to in wild-type mice
• however, treatment with doxycycline after the onset of symptoms restores some of the caudate putamen area
• gliosis spreads throughout the lateral and medial striatum over time
• mice exhibit reactive astrocytosis in the striatum that spreads over time
• however, treatment with doxycycline after the onset of symptoms reduces astrocytosis
• mice develop neuronal intranuclear and extranuclear inclusion
• however, treatment with doxycycline after the onset of symptoms alleviates inclusions

behavior/neurological
• in older mice with tremors
• beginning at 4 weeks, some mice exhibit limb grasping when suspended
• by 8 weeks, all mice display clasping that can last after mice are released
• however, treatment with doxycycline after the onset of symptoms reduces glasping behavior and duration
• mild tremors begin at 20 weeks in some mice
• in some mice tremors develop into a jerking motion
• mice exhibit progressive motor dysfunction with choreic and dystonic movements, and parkinsonism
• at 36 weeks

muscle
• mice exhibit progressive motor dysfunction with choreic and dystonic movements, and parkinsonism

Mouse Models of Human Disease
OMIM IDRef(s)
Huntington Disease; HD 143100 J:61490


Mouse Genome Informatics
cx41
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-DISC1*)1001Plet/0

involves: C57BL/6 * CBA * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• spatial memory in females is impaired in probe trials, with females spending less time in the target quadrant where the platform had previously been
• male mutants show higher degree of spontaneous locomotor activity than wild-type littermate controls during a 20-hour period
• male mutants spend significantly less time in non-aggressive social interaction with other males
• males display increased aggressiveness toward other males, with an increase in number of attacks

nervous system
• volume is significantly increased, with no change in total brain volume
• cultured control neurons grow more complex neurite arbors than mutant neurons (for 20-100 um rings centered on neuron soma)


Mouse Genome Informatics
cx42
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-COX8A/PstI*)1Ctm/0

involves: C57BL/6 * CBA * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants grown in the presence of Dox from E0 to P21 become progressively less active after the removal of Dox and die before 100 days of age

behavior/neurological
• mutants grown in the absence of Dox develop an abnormal limb-clasping behavior at 2 months of age
• mutants grown in the presence of Dox from E0 to P21, however, do not exhibit this limb-clasping behavior
• mutants grown in the presence of Dox from E0 to P21 become progressively less active after the removal of Dox and die before 100 days of age


Mouse Genome Informatics
cx43
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-CDK5R1/GFP)337Lht/0

involves: C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size/body
• transgenic mice with transgene expression induced by removal of doxycycline from their food 4-6 weeks postnatal exhibit a slightly decreased body weight compared to control littermates

nervous system
• transgenic mice with induction of expression of the transgene for different time periods display progressive decrease in brain weight; with induction for 5 weeks there is a 15-20% decrease in brain weight and with more than 12 weeks of induction, the weight decrease is 30%
• in transgenic mice induced for 8 and 12 weeks, there is an increase in aggregations of tau protein (insoluble tau) with an increased amount of phosphorylated tau present; at 15 weeks, there is less soluble tau than in wild-type forebrains and similar results are found at 27 weeks of induction
• brains of transgenic mice induced for 12 weeks show a significant decrease in thickness and neuronal density in the hippocampus compared to controls
• brains of transgenic mice induced for 12 weeks show a significant decrease in thickness and neuronal density in the cerebral cortex compared to controls; mice induced for 8 or 12 weeks show a 25 or 40% decrease in cortical neuronal density, respectively, whereas wild-type or non-induced transgenic mice had the same neuronal density
• induced transgenic mice at 12 weeks postnatal display significant forebrain atrophy with decrease in forebrain mass
• neurofibrillary tangle-like pathology is exhibited in brains of transgenic mice induced for 27 weeks; there are numerous intraneuronal and flame-shaped neurons positive for neurofibrillary tangle-specific proteins in the cortex and hippocampus of transgenic mice but not wild-type
• other methosds also identify neurofibrillary tangle-like structures in the cerebral cortex, hippocampus and entorhinal cortex of transgenic mice
• brains of transgenic mice induced for 8 or 12 weeks do not express markers for late stage tangles similar to what is observed in wild-type
• reactive astrogliosis is increased throughout the cortex and hippocampus of mutants evident by an increase in radial and stellate-shaped astrocytes


Mouse Genome Informatics
cx44
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-Rai1,-EGFP)463Walz/0

involves: C57BL/6J * CBA/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size/body
• mutants start to show lower weight at 4 months of age

behavior/neurological
• mutants show less freezing in the contextual fear test, indicating that learning and/or memory are impaired
• mutants show less freezing in the sound cued fear tests, indicating that learning and/or memory are impaired
• in the open field, mutants show an increase in total distance traveled indicating hyperactivity
• however anxiety-like behavior is not observed and mice show normal sociability and preference for social novelty
• lower percentage of vocalization, with mutants showing 17% vocalization compared to 29% in wild-type mice

adipose tissue

Mouse Models of Human Disease
OMIM IDRef(s)
Potocki-Lupski Syndrome; PTLS 610883 J:207141


Mouse Genome Informatics
cx45
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-Rai1,-EGFP)479Walz/0

involves: C57BL/6J * CBA/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size/body
• mutants start to show lower weight at 2 months of age
• mutants treated with Dox to turn off transgene expression from conception to 3 months of age show normal weight
• Dox administration from 1 to 3 months of age to turn off transgene expression before the onset of abnormalities is seen does not prevent abnormal phenotypes, with mutants developing lower weight from 9 weeks of age
• Dox administration from 3 to 5 months of age to turn off transgene expression after the onset of abnormal phenotypes does not result in recovery after 2 months of Dox treatment

behavior/neurological
• mutants show less freezing in the contextual fear test, indicating that learning and/or memory are impaired
• mutants treated with Dox to turn off transgene expression from conception to 3 months of age show normal contextual memory
• Dox administration from 1 to 3 months of age to turn off transgene expression before the onset of abnormalities is seen does not prevent abnormal phenotypes, with mutants developing impaired learning and memory in the fear contextual conditioning test
• mutants show less freezing in the sound cued fear tests, indicating that learning and/or memory are impaired
• mutants treated with Dox to turn off transgene expression from conception to 3 months of age still show impaired memory in the sound cue test
• Dox administration from 1 to 3 months of age to turn off transgene expression before the onset of abnormalities is seen does not prevent abnormal phenotypes, with mutants developing impaired learning and memory in the cued conditioning tests
• in the open field, mutants show an increase in total distance traveled indicating hyperactivity
• however anxiety-like behavior is not observed and mice show normal sociability and preference for social novelty
• mutants treated with Dox to turn off transgene expression from conception to 3 months of age show normal activity
• Dox administration from 1 to 3 months of age to turn off transgene expression before the onset of abnormalities is seen does not prevent abnormal phenotypes, with mutants developing hyperactivity
• lower percentage of vocalization, with mutants showing 8% vocalization compared to 29% in wild-type mice

adipose tissue
• mutants show lower abdominal fat weight
• mutants treated with Dox to turn off transgene expression from conception to 3 months of age show normal abdominal fat weight

Mouse Models of Human Disease
OMIM IDRef(s)
Potocki-Lupski Syndrome; PTLS 610883 J:207141


Mouse Genome Informatics
cx46
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LMNB1)AF1Yfu/0

involves: FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
N
• normal motor behavior (J:197168)


Mouse Genome Informatics
cx47
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-MAPT*P301L)#Kha/0

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• reduction in exploration in open-field tests
• mutants first exhibit impaired spatial reference memory at 2.5 months of age, showing a slightly reduced search bias for the target quadrant than controls in the Morris water maze
• spatial memory retention becomes more impaired with age, especially after 4 months of age, with the mean probe performance being equal to random swimming, indicating little or no retention of spatial memory
• mutants exhibit cognitive impairments in the acquisition phases of the Morris water maze, showing a longer mean distance to locate the hidden platform
• clasping and limb retraction when lifted by the tail
• mutants exhibit longer latencies to traverse a beam
• mutants develop an age-dependent increase in the time taken to start swimming, however they are able to achieve comparable mean swim speeds during probe trials
• from about 9.5 months of age, the most severely affected mutants develop hunched posture with hindlimb dysfunction and tail rigor
• develop dystonic posture with tail rigor at 9.5 months of age
• from about 9.5 months of age, the most severely affected mutants exhibit decreased ambulation

growth/size/body
• from about 9.5 months of age, the most severely affected mutants exhibit decreased body weight

nervous system
• 4-7% reduction in brain weight at 4 months of age
• atrophy of the forebrain is seen by 5 months of age
• age-dependent progression of tau processing that results in pathophysiological deposition of tau as mature tangles in the brain
• mutants exhibit age-dependent progression of neurofibrillary tangle formation, with tangles first appearing in the neocortex and then progressing into the hippocampus and limbic structures with increasing age
• neurofibrillary tangles develop in the hippocampus in a distinct pattern; mature tangles occur initially in CA1 pyramidal neurons, spread to CA2, and by 8.5 months of age include pyramidal neurons in CA2 and granular neurons of the dentate gyrus
• abnormal conformations of tau are present in the hippocampus and neocortex of 2.5-month old mutants
• reactive astrocytes in forebrains of 10 month old mutants
• atrophy of the dorsal corticospinal tracts accompanied by loss of neurofilament
• degeneration in the hippocampus and neocortex is seen in 10 month old mutants
• massive neuronal loss, most apparent in the CA1 region of the hippocampus
• spinal cords appear thinner, however, no decrease in motor neuron density is seen

muscle
• develop dystonic posture with tail rigor at 9.5 months of age


Mouse Genome Informatics
cx48
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2*G2019S)1Cai/0

Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• total neurite length is shortened compared to in wild-type mice
• neurons produce fewer neurites than in wild-type mice
• however, doxycyclin or forskolin treatment rescues the inhibited neurite growth
• the longest process corresponding to the axon is reduced in length compared to in wild-type mice


Mouse Genome Informatics
cx49
    Tg(Camk2a-tTA)1Mmay/0
Tg(tetO-LRRK2)1Cai/0

Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
N
• neuronal processes are normal (J:154755)


Mouse Genome Informatics
tg50
    Tg(Camk2a-tTA)1Mmay/0
(B6.Cg-Tg(Camk2a-tTA)1Mmay x 129X1/SvJ)F1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• Background Sensitivity: freezing in response to unsignaled foot shock decreases in mutant and increases in control during final minutes of 5 minute test

nervous system
• Background Sensitivity: width of granule cell layer is 27% thinner than controls and the C57BL/6 congenic background
• Background Sensitivity: width of granule cell layer is 27% thinner than controls and the C57BL/6 congenic background


Mouse Genome Informatics
tg51
    Tg(Camk2a-tTA)1Mmay/0
(B6.Cg-Tg(Camk2a-tTA)1Mmay x C3H/HeJ)F1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• Background Sensitivity: width of granule cell layer is 14% thinner than controls and the C57BL/6 congenic background
• Background Sensitivity: width of granule cell layer is 14% thinner than controls and the C57BL/6 congenic background


Mouse Genome Informatics
tg52
    Tg(Camk2a-tTA)1Mmay/0
(B6.Cg-Tg(Camk2a-tTA)1Mmay x C3H/HeJ)F1 x C3H/HeJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• Background Sensitivity: width of granule cell layer is 29% thinner than controls and C57BL/6 congenic background
• Background Sensitivity: width of granule cell layer is 29% thinner than controls and C57BL/6 congenic background


Mouse Genome Informatics
tg53
    Tg(Camk2a-tTA)1Mmay/0
(B6.Cg-Tg(Camk2a-tTA)1Mmay x CBA/J)F1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• Background Sensitivity: width of granule cell layer is 30% thinner than controls and the C57BL/6 congenic background
• Background Sensitivity: width of granule cell layer is 30% thinner than controls and the C57BL/6 congenic background


Mouse Genome Informatics
tg54
    Tg(Camk2a-tTA)1Mmay/0
(B6.Cg-Tg(Camk2a-tTA)1Mmay x DBA/1J)F1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• Background Sensitivity: width of granule cell layer is 17% thinner than controls and the C57BL/6 congenic background
• Background Sensitivity: width of granule cell layer is 17% thinner than controls and the C57BL/6 congenic background


Mouse Genome Informatics
tg55
    Tg(Camk2a-tTA)1Mmay/0
(B6.Cg-Tg(Camk2a-tTA)1Mmay x FVB/NJ)F1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• Background Sensitivity: width of dentate gyrus granule cell layer is 21% thinner than controls and the C57BL/6 congenic background
• however, doxycycline administered in the first 6 weeks of life protects against cell loss
• Background Sensitivity: width of dentate gyrus granule cell layer is 21% thinner than controls and the C57BL/6 congenic background
• however, doxycycline administered in the first 6 weeks of life protects against cell loss


Mouse Genome Informatics
tg56
    Tg(Camk2a-tTA)1Mmay/0
involves: C3H/HeJ * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• Background Sensitivity: granule cell layer of the dentate gyrus is reduced and disorganized in 2 month old mice as compared to non-transgenic controls and the C57BL/6 congenic background
• Background Sensitivity: cell loss is not observed in 2 week old mice
• Background Sensitivity: width of granule cell layer is 42% thinner than controls by 2-4 months
• Background Sensitivity: width of granule cell layer is 68% thinner than controls by 6-9 months
• however, when mice are reared on doxycycline, cell loss is not observed
• neuronal degeneration is progressive


Mouse Genome Informatics
tg57
    Tg(Camk2a-tTA)1Mmay/?
B6.Cg-Tg(Camk2a-tTA)1Mmay
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• mice swim less distance in the target quadrant than controls when tested for long-term recall suggesting a memory consolidation impairment

nervous system
N
• Background Sensitivity: no evidence of overt dentate degeneration on the C57BL/6 congenic background as compared to C3H/He and CBA genetic backgrounds (J:185792)
• granule cell layer is similar to control at all time points studied (J:185792)