Species: Mouse
Genes: SNCA
Modification: SNCA: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: B6;DBA-Tg(Thy1-SNCA)61Ema
Genetic Background: (C57BL/6 x DBA/2)F1 (strain of origin)
Availability: Available through Eliezer Masliah, Robert Rissman for academic research; others please contact the Office of Innovation and Commercialization at the University of California, San Diego. The CRO Scantox Neuro offers research services with this model.

Summary
The Thy1-αSyn mouse model, a.k.a. Line 61, overexpresses human α-synuclein under the Thy1 promoter (Rockenstein et al., 2002). It is one of the most extensively characterized animal models of Parkinson’s disease (PD), and reproduces several features of the sporadic disease (Chesselet et al., 2012). Notably, these transgenic mice develop progressive changes in the striatal content and release of dopamine, α-synuclein pathology, motor and nonmotor impairments associated with pre-manifest and manifest PD, inflammation, and PD-like changes in biochemical and molecular pathways. They lack the loss of dopaminergic neurons in the substantia nigra, however—a hallmark of PD— although they undergo a progressive loss of these cells’ terminals.

Many of the behavioral and pathological deficits that arise in Line 61 mice have been reproduced in multiple labs. Moreover, power analyses of several endpoint measures indicate that relatively small cohorts (two to 20 mice) are sufficient to detect treatment effects of a 30–50 percent magnitude with high likelihood in preclinical studies (Chesselet et al., 2012). In addition, characterization of this mouse model includes assessments, such as EEG recordings, that are well suited to clinical translation.

However, some phenotypes appear to express differently between labs. While early deficits are very reproducible, the time course of later impairments may vary (Marie-Françoise Chesselet, 2019, personal communication). Differences in housing and feeding may contribute to these discrepancies. Indeed, variations in the gut microbiome have been reported to affect the expression of motor deficits, microglial activation, and α-synuclein pathology (Sampson et al., 2016).

Characterization studies of Line 61 mice have been carried out in the original genetic background, C57BL/6 x DBA/2, as well as in fully backcrossed C57B16 mice. The deficits observed in the two backgrounds appear to be similar, but the characterization of the mixed background is much more extensive (Chesselet et al., 2012). Use of the fully backcrossed line is limited by small litters and earlier ages at death.

Also of note, additional mouse models that overexpress human α-synuclein under the Thy1 promoter have been created, but they are not equivalent and their phenotypes differ significantly.

General health | Transgene expression | Neuron loss | Dopamine deficiency | α-Synuclein aggregates | Neuroinflammation | Mitochondrial abnormalities | Motor impairment | Non-motor impairments | Alterations in electrophysiological and molecular networks | Modification details

General health
Before 14 months of age, the mortality and morbidity rates, as well as the general health, of Line 61 mice are similar to those of wild-type mice, although male body weight starts lagging behind that of non-transgenic mice at 4 months of age (Chesselet 2012). Robust motor deficits surface early, but parkinsonian-like motor impairment develops only until approximately 14 months, coinciding with robust dopamine loss in the striatum. Survival of transgenic mice after this age can be improved by providing moistened mashed food and minimizing stress.

Transgene expression
Female Line 61 mice express lower levels of the human α-synuclein transgene because it is inserted in the X chromosome, which undergoes random chromosomal inactivation (Chesselet et al., 2012). Also of note, transgene expression begins at postnatal day 10, so it does not interfere with embryonic development.

Once transgene expression stabilizes, the protein is detectable throughout the brain, including the dopaminergic neurons of the substantia nigra pars compacta which are severely affected in PD. Measurements of both the transgene mRNA, in tissue isolated by laser-capture microdissection, and the transgene protein, detected by immunohistochemistry, have confirmed expression in this PD-relevant brain region.

The expression of the protein ramps up steadily after postnatal day 10, however, there is some variation between brain regions. In the hippocampus, for example, protein levels are robust by 2 months of age, and continue to increase at least until 6 months of age (Rabl et al., 2017). However, expression in the striatum slightly decreases or stays constant between 2 and 6 months. This pattern parallels murine α-synuclein expression, which drops in the striatum in both transgenic and non-transgenic mice. It also suggests a lack of direct correspondence between transgene levels and the progression of motor and cognitive deficits. Moreover, murine α-synuclein levels are slightly lower in transgenic mice compared with non-transgenic controls, possibly because overexpression of the human protein downregulates endogenous expression.

In contrast to other mouse models carrying the human α-synuclein gene under the Thy1 promoter, Line 61 mice express the protein at moderate levels throughout the brain (Rockenstein et al., 2002; Chesselet et al., 2012). Histological measurements using an antibody that detects both mouse and human α-synuclein revealed a 1.5- to 3.4-fold elevation of α-synuclein in most brain areas compared with wild-type mice, with higher levels in the thalamus (6.5-fold). Similar results were obtained using western blots, although in this case, cerebellar levels surpassed those of the thalamus. Interestingly, brain α-synuclein levels in Line 61 mice are in the range of those expected in individuals with α-synuclein gene triplication, a cause of familial PD. Of note, overexpression of α-synuclein protein was also reported in peripheral neurons, including the cholinergic neurons that innervate the colon, which may contribute to intestinal dysfunction.  

Neuron loss
Motor neuron pathology has not been detected in these mice (Rockenstein et al., 2002; Chesselet et al., 2012). Even at 22 months of age, transgenic mice did not show any reduction in the number of neurons expressing tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis, in the substantia nigra pars compacta, although their diameters were slightly reduced. Interestingly, a progressive accumulation of iron deposits in this brain region was observed at 5, 12, and 22 months of age, similar to postmortem observations in PD brains.

Neuronal loss in other brain regions does occur, however. One study found fewer neurons in the deeper layers of the neocortex and CA3 area of the hippocampus in transgenic mice at 3 to 4 months of age than it did in non-transgenic animals (Overk et al., 2014). Subsequent studies confirmed neuronal loss in the neocortex and hippocampal CA3 region at 6 and 9–10 months of age (Wrasidio et al., 2016; Price et al., 2018; Kim et al., 2018).

Dopamine deficiency
Line 61 mice lose striatal dopamine progressively after a temporary increase in the neurotransmitter’s extracellular levels. At 6 months of age, in vivo microdialysis revealed elevated levels of tonic striatal extracellular dopamine and dopamine metabolite 3-methoxytyramine, alterations that were accompanied by hyperactivity in the open field (Lam et al., 2011). Interestingly, in some labs but not others, a reduction in TH immunolabeling in the striatal neuropil was reported at this age, and a reduction in striatal dopamine transporter (DAT) levels (Kim et al., 2015; Wrasidio et al., 2016; Price et al., 2018). Extracellular dopamine levels normalized between 8 and 12 months of age, and then began to drop. By 14 months, they were at approximately 60 percent of controls (Lam et al., 2011). TH levels were also reduced at this age, but only by approximately 20 percent.

α-Synuclein aggregates
α-Synuclein aggregates resistant to proteinase K treatment, which correlate with Lewy body pathology in human disease, are detectable in the brains of Line 61 mice as early as 1 month of age (Chesselet et al., 2012). They range in size from <1 μm to 16 μm, with the larger ones sometimes covering the entire neuronal cell body. In 1-month-olds, small puncta are abundant in the dorsal nucleus of the vagus and olfactory bulb, whereas larger aggregates are found throughout the thalamus, including the dorsal lateral geniculate nucleus, the locus coeruleus, and the cerebellum. The size and number of aggregates increase with age. At 5 months, variable-sized deposits are detected in the substantia nigra and periaqueductal gray area (Grant et al., 2014).

Interestingly, the size of α-synuclein proteinase K-resistant aggregates varies greatly between different brain regions, independently of transgene expression levels. For example, whereas small aggregates populate the cortex and the striatum, much larger deposits are found in the substantia nigra (Chesselet et al., 2012; Price et al., 2018).

Elevated levels of α-synuclein phosphorylated at serine 129, a hallmark of human Lewy bodies, have been found in the ventral mesencephalon/substantia nigra, striatum, cortex, frontal cortex, and hippocampus of Line 61 mice. In hippocampal region CA1, a subset of pyramidal neurons express particularly high levels of the phosphorylated species (Rabl et al., 2017). In contrast, in the thalamus, cerebellum, and olfactory bulb, the protein’s levels are similar to those of wild-type mice (Chesselet et al., 2012). Interestingly, whereas in the cortex, hippocampus, and substantia nigra of non-transgenic mice the phosphorylated form is mostly found in nerve terminals, in transgenic mice, it accumulates in the cell soma and nucleus.

In addition, C-terminal fragments of α-synuclein, which are thought to contribute to α-synuclein oligomerization and toxicity, co-localize with dystrophic neurites in cortical and subcortical regions of Line 61 mice, including layers 2 and 3 of the neocortex, the stratum lacunosum, the dentate gyrus, area CA3 of the hippocampus, as well as the striatum, thalamus, midbrain, and pons (Games et al., 2013).

Accumulation of α-synuclein also has been reported in peripheral neurons. In the myenteric plexus of the distal colon of 8- to 10-month-old mice, cholinergic neurons, in particular, are surrounded by terminals enriched in α-synuclein, although proteinase K-resistant aggregates are absent (Wang et al., 2012). This accumulation may contribute to impaired defecation in response to stress.

α-Synuclein also builds up in glial cells. In the cortices of 9- to 10-month-old transgenic mice, the astrocyte marker GFAP was reported to co-localize with human α-synuclein (Kim et al., 2018).

Of note, Line 61 mice raised under germ-free conditions had fewer α-synuclein aggregates in the caudoputamen, substantia nigra, and frontal cortex than transgenic mice harboring a complex microbiota at approximately 3 months of age (Sampson et al., 2016). No differences in aggregate load were observed in the cerebellum.

Neuroinflammation
Signs of neuroinflammation have been detected in Line 61 mice at a young age. In the striatum, activated microglia and increased levels of the cytokine TNF-α have been reported at 1 month of age (Watson et al., 2012). Moreover, in 6- to 10-month-old mice, elevated levels of the astroglial marker GFAP and the microglial marker Iba-1 were observed in the neocortex, striatum, and hippocampus, as were several cytokines in the cortex, including interleukin 1β, TNFα, and interleukin 6, and activation of NFκB and caspase-3 (Rockenstein et al., 2014; Kim et al., 2015; Price et al., 2018; Valera et al., 2015; Wrasidio et al., 2016; Kim et al., 2015; Kim et al., 2018).

Results have not been entirely consistent across studies, however. Rabl and colleagues, for example, detected astrogliosis and activated microglia at 6 and 9 months in cortex and hippocampus, but the levels were similar to those observed in non-transgenic littermates (Rabl et al., 2017). Also, in contrast to other studies, Watson and colleagues failed to detect microglial activation in the cortex (Watson et al., 2012). Differences in antibodies, cortical regions surveyed, and/or genetic divergence of mouse colonies may explain the discrepancies (Rabl et al., 2017). In addition, differences in the gut microbiomes of mice in different labs may contribute to variability. Indeed, at approximately 3 months of age, microglial activation in the caudoputamen and substantia nigra of transgenic mice raised in germ-free conditions was robustly reduced compared with that of transgenic mice harboring normal gut flora (Sampson et al., 2016).

The profile and time course of neuroinflammation vary between affected areas. For example, whereas the striatum showed signs of very early microglial activation and TNF-α elevation at 1 month of age, these alterations surfaced in the substantia nigra at 5–6 months of age, and remained undetectable in cortex and cerebellum in the same study (Watson et al., 2012). Moreover, while IL-1β was reported as elevated in the cortices of 6- to 10-month-old mice (Kim et al., 2015; Kim et al., 2018), it remained unchanged, as did TGF-β, in the striatum and substantia nigra (Watson et al., 2012). Microglial activation persisted at 14 months of age in the striatum whereas it considerably decreased at this older age in the substantia nigra (Watson et al. 2012; Subramaniam et al., 2018). This sign of transient neuroinflammation in the substantia nigra is consistent with the inflammation seen in early, but not advanced, stages of PD.

The expression of toll-like receptors (TLRs) 1, TLR 4, and TLR 8, pro-inflammatory receptors that may mediate microglial activation, appears to be increased at 5–6 months in the substantia nigra, but not in the cerebral cortex, and TLR 2 is increased in the substantia nigra at 14 months of age (Watson et al., 2012). Interestingly, TLR 2 has been implicated in neuron-to-neuron and neuron-to-astrocyte transmission of α-synuclein, and a subsequent study reported it increased in neurons, astrocytes, and microglia in the neocortex of 9- to 10-month-old transgenic mice (Kim et al., 2018).

In older Line 61 mice, the adaptive immune system appears to be activated. Peripheral CD4 and CD8-postive T cells in the blood were found to be increased at 22 months of age (Watson et al., 2012).

Mitochondrial abnormalities
The mitochondrial respiratory complexes of Line 61 mice are impaired, particularly in brain regions that contain nigrostriatal dopaminergic neurons (Subramanian et al., 2015). The activities of complexes I, II, IV, and V in mitochondria isolated from the midbrains of 6-month-old transgenic mice were reduced compared with those of non-transgenic littermates, and in the striatum, the functions of complexes IV and V were altered. Midbrain defects in complex I activity were detected at 4 months of age as well. In both the midbrain and striatum, as well as in cortex, α-synuclein accumulation in mitochondria was two- to fourfold higher than in wild-type organelles.

Consistent with the functional disruption, which can contribute to oxidative stress, high levels of lipid peroxidation were observed in the ventral midbrain of 5- to 6-month-old transgenic mice. Interestingly, in this brain region, levels of the reduced form of peroxiredoxin 2, a neuronal antioxidant, were decreased, whereas levels of its oxidized form were increased at 8 months of age. In contrast, in striatum and cortex, the reduced form of the antioxidant was increased.

Motor impairment
Line 61 mice develop different motor impairments at different stages of life (Chesselet et al., 2012). As early as 1 month of age, their performance on the wire hanging test, which assesses balance, coordination, and muscle strength, is reduced compared with non-transgenic littermates, and it worsens with age (Rabl et al., 2017). Transgenic mice also build poorer-quality nests at this age and their skills don’t improve as those of wild-type animals do. At 2 months, their latency to fall off the rotarod is reduced compared with controls, and performance on challenging motor tests, such as a beam overlaid with a grid or the pole test, is also compromised (Fleming et al., 2004; Chesselet et al., 2012; Rabl et al., 2017). Front limb, and particularly hind limb, movements, including rearing, in a transparent cylinder are also reduced at this early age. These impairments worsen progressively, and are severe at 14 months of age, particularly in males. Grip strength deficits also arise at an early age, reported in mice as young as 3 months old (Price et al., 2018).

Fine motor skills are also impaired. For example, at 3 months, transgenic mice bite into pieces of pasta at a lower frequency than controls (Rabl et al., 2017). Moreover, at 4, and particularly 8 months of age, they are less dexterous at picking up cotton to build a nest or extracting a pellet from a hole, than wild-type mice (Fleming et al., 2004; Magen et al., 2012). Also, at 8 months, grooming is reduced (Fleming et al., 2006).

Similar to other mouse models that overexpress α-synuclein, Line 61 mice go through a transient period of hyperactivity, between approximately 4 and 9 months of age, in which they travel more distance and more rapidly in an open field arena than wild-type mice, and climb on a mesh cylinder more often and more quickly (Chesselet et al., 2012; Wrasidio et al., 2016; Kim et al., 2018). This hyperactive stage correlates with the onset of neuron loss and neurite degeneration in the neocortex, CA3 region of the hippocampus, and striatum, and increased astrogliosis in the frontal cortex and striatum (Wrasidio et al., 2016). It also coincides with the emergence of alterations in cortico-striatal function (Watson et al., 2009; Wu et al., 2010).

When Line 61 mice are hyperactive, they also make more motor errors, such as increased foot slips when walking over a round beam (Kim et al., 2015). This alteration appears to persist, however, as it was also reported in 10- and 12-month-old mice (Valera et al., 2015; Games et al., 2014).

Cranial sensorimotor deficits, which in humans manifest prior to typical PD motor deficits and include disruptions in speech, voice, and swallowing, also have been reported to arise early in Line 61 mice. In particular, the duration, intensity, and profile of male vocalizations were found to be altered as early as 2 to 3 months of age (Grant et al., 2015).

Line 61 mice also suffer from colonic motor dysfunction (Wang et al., 2008; Wang et al., 2012). Mice as young as 2.5 months old produce fewer fecal pellets when exposed to a stressful stimulus than wild-type mice, an alteration that persisted at least until 8 months of age.

Later in life, Line 61 mice begin exhibiting symptoms similar to those associated with manifest PD. In particular, at approximately 15 months of age, they show hypoactivity in the open field, and take longer to remove a small adhesive label from their snouts, a test of sensorimotor function. Consistent with this deficit occurring after striatonigral dopamine loss is evident, it could be reversed by L-dopa, whereas impairments that arise earlier seem to worsen with such treatment, as expected given the excess of extracellular dopamine in the striatum at that age (Lam et al., 2011; Fleming et al., 2006). Late-expressing deficits progress with aging and other impairments arise, including difficulty eating, akinesia, and hunched posture (Chesselet et al., 2012).

Interestingly, Line 61 mice raised under germ-free conditions perform several motor tasks, including beam traversal, pole descent, adhesive removal, hind-limb clasping, and defecation, significantly better than transgenic mice harboring a complex gut microbiome at approximately 3 months of age (Sampson et al., 2016).

Non-motor impairments
Several PD-related, non-motor impairments also have been reported in these mice, including disruptions in olfaction, circadian rhythms, sleep, cognition, social behavior, and autonomic function. At 3 and 9 months of age, transgenic mice scored poorly on three different olfactory tests (Fleming et al., 2008). Both odor detection and odor discrimination were affected, without total loss of smell, and the deficits were not progressive, similar to the olfactory impairments reported in PD patients. Transgenic mice accumulate α-synuclein aggregates in the olfactory bulb, and may also have deficits in neurogenesis in this brain region.

Circadian rhythms also are altered in Line 61 mice (Kudo et al., 2011). As early as 3–4 months of age, their amplitude dampens and activity/rest cycles become fragmented. These alterations worsen progressively up to 12 months of age. Moreover, sleep dysregulation, reminiscent of that experienced by PD patients, has also been observed (McDowell et al., 2014). Ten-month-old transgenic males spend more time in non-rapid eye movement (non-REM) sleep and less time in REM sleep during their rest phase than non-transgenic males. In addition, during their active phase, they spend more time awake and less time in REM sleep. Similar to observations in patients, the power spectra of EEG recordings is shifted toward lower frequencies, with a decrease in gamma power during wakefulness (McDowell et al., 2014; Morris et al., 2015).

Cognitive deficits are also observed in these mice (Magen et al., 2012). At 4 to 6 months of age, Line 61 mice score lower than non-transgenic littermates in the test of spontaneous alternation in the Y-maze, as well as in tests of novel object recognition, object-place recognition, and operant reversal learning. Similar to PD patients, the mice appear to be capable of learning rules as well as control animals, but have trouble switching to new rules involving changes in sequence. In addition, at 7–8 months of age, but not earlier, emotional learning and social cognition are impaired, which is reminiscent of deficits in Theory of Mind reported in patients (Magen et al., 2015). Moreover, one study reported less freezing behavior in the fear conditioning task compared with non-transgenic littermates at 8 months of age (Rabl et al., 2017).

Autonomic cardiovascular function is also affected in Line 61 mice (Fleming et al., 2013). In particular, the sympathetic and parasympathetic regulation of heart rate is disrupted in males at 9–10, as well as 3–5, months of age.

Alterations in electrophysiological and molecular networks

Corticostriatal transmission is impaired soon after birth in Line 61 mice. At 35, but not 21, days of age, the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in medium spiny cells of the striatum was reduced compared with that of wild-type mice, and the reduction worsened at 3 and 10 months of age (Wu et al., 2010). Decreased neurotransmitter release appears to underlie this disruption.  In addition, at 3 months, the frequency of spontaneous GABA-A receptor-mediated synaptic currents was decreased in medium spiny neurons, but increased in cortical pyramidal neurons. Presynaptic plasticity is also impaired, possibly because of reduced glutamate at corticostriatal synapses caused by altered adenylyl cyclase signaling (Watson et al., 2009).

Moreover, the early elevation of extracellular dopamine observed in the striatum of transgenic mice appears to have an impact on corticostriatal function. Indeed, dopaminergic modulators affect corticostriatal glutamate release in transgenic mice differently than in non-transgenic animals. For example, while amphetamine reduced sEPSC frequency in wild-type animals, it had no effect in Line 61 mice. Consistently, amphetamine treatment failed to improve the reduced grooming observed in transgenic animals (Fleming et al., 2006).  These data suggest that circuitry changes emerge well before the loss of striatal dopamine, and might explain early behavioral deficits (Chesselet et al., 2012).

Line 61 mice also have been reported to overexpress mGluR5 receptors, which co-localize with α-synuclein, in the hippocampus and basal ganglia.  Consistent with this alteration, impaired performances in the water maze and pole test were reversed with the mGluR5 antagonist, MPEP (Price et al., 2010).

Transcriptomic analyses of the striata of 6-month-old transgenic mice revealed alterations in the expression of genes involved in synaptic plasticity, signaling, transcription, apoptosis, and neurogenesis (Cabeza-Arvelaiz et al., 2011).

Modification details
This transgenic mouse expresses human wild-type α-synuclein under the control of the mouse Thy1 promoter (Rockenstein et al., 2002). The transgene is inserted in the X chromosome.

Phenotype Characterization

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References

Paper Citations

1. Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, Masliah E. Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res. 2002 Jun 1;68(5):568-78. PubMed.
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4. Rabl R, Breitschaedel C, Flunkert S, Duller S, Amschl D, Neddens J, Niederkofler V, Rockenstein E, Masliah E, Roemer H, Hutter-Paier B. Early start of progressive motor deficits in Line 61 α-synuclein transgenic mice. BMC Neurosci. 2017 Jan 31;18(1):22. PubMed.
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12. Games D, Seubert P, Rockenstein E, Patrick C, Trejo M, Ubhi K, Ettle B, Ghassemiam M, Barbour R, Schenk D, Nuber S, Masliah E. Axonopathy in an α-synuclein transgenic model of Lewy body disease is associated with extensive accumulation of C-terminal-truncated α-synuclein. Am J Pathol. 2013 Mar;182(3):940-53. PubMed.
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33. Cabeza-Arvelaiz Y, Fleming SM, Richter F, Masliah E, Chesselet MF, Schiestl RH. Analysis of striatal transcriptome in mice overexpressing human wild-type alpha-synuclein supports synaptic dysfunction and suggests mechanisms of neuroprotection for striatal neurons. Mol Neurodegener. 2011 Dec 13;6:83. PubMed.

Other Citations

1. Eliezer Masliah

External Citations

1. Scantox Neuro

Further Reading

No Available Further Reading