• die at 3-4 months of age

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

• 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

• 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

• 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

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

• 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 Gabrg2^tm2Spet 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

• 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 Gabrg2^tm2Spet 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 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

• increased activity begins at 6 weeks of age and persists at least until 16 months of age

• in an open field test, mice exhibit increased vertical activity compared with wild-type mice

• however, treatment with methylphenidate or haloperidol suppresses vertical activity

• in an open field box, mice fail to build a nest unlike wild-type mice

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

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

• progressive atrophy of dentate granule cells

• progressive atrophy of hippocampal pyramidal neurons

• 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

• gross atrophy of the forebrain was evident in a 10-month-old mouse

• significant decrease in total numbers of CA1 hippocampal neurons

• CA1 neuron estimates were stabilized after brief (6- to 8-week) doxycycline treatment

• approximately 23% of CA1 pyramidal cells remaining at 8.5 months

• CA1 neuron estimates were stabilized after brief (6- to 8-week) doxycycline treatment

• 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

• 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

• 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

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

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

• 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)

• 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

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

• 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

• 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

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

• no acceleration of degeneration is observed compared to Tg(Camk2a-tTA)1Mmay/Tg(tetO-LRRK2*G2019S)E3Cai mice (G2019S)

• mice exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus

• 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

• 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 exhibit a progressive neuronal atrophy that is most pronounced in the granule cell layer of hippocampal dentate gyrus

• 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

• 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 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

• 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

• 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

• 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

• 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

• 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

• 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

• suppression of transgene expression in these mice is most sensitive to doxycycline of the four lines tested

• 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

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

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

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

• 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 glisosis 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

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

• mice appear normal and healthy, and expression of EYFP is detected in neuronal mitochondria under appropriate conditions

• 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

• no neuronal degeneration is observed at 1 month in the striatum or cortex of LRRK2WT-L mice (J:156512)

• 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

• increasing accumulation of alpha-synuclein is detected in cell bodies at 1 month

• neurodegeneration is accelerated in the striatum

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

• increased microglial activation is observed in the brain

• increased microglial activation is observed in the brain

• increased framentation of the Golgi complex is observed in KD mice

• 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

• 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

• 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

• 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

• 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

• 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 microglial activation are higher than in A53T/LRRK2WT mice

• 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

• 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

• 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

• 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

• 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)

• increased microglial activation is observed in the brain

• increased microglial activation is observed in the brain

• 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

• at 2 months of age, mice show drastically increased ambulatory activity

• mice display elevated rearing activities at 6 months of age

• 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

• in 6 month old mice but not in nontransgenic controls, elevated levels of ubiquitin are detected in somas and nuclei of cortical neurons, but

• neuron loss is detected at 6 months and later

• 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

• 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

• 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

• significant at 12 months

• 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

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

• somatic alpha synuclein in neurons is apparent at 1 month

• no alpha-synuclein accumulation is observed in neurons at 1 month (J:156512)

• 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

• 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

• 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

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

• 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

• 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)

• 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

• 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

• 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

• 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%

• induced transgenic mice at 12 weeks postnatal display significant forebrain atrophy with decrease in forebrain mass

• 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

• 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

• 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

• neuronal processes are normal (J:154755)

• Background Sensitivity: freezing in response to unsignaled foot shock decreases in mutant and increases in control during final minutes of 5 minute test

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• mice swim less distance in the target quadrant than controls when tested for long-term recall suggesting a memory consolidation impairment

• 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)