Modification: SNCA: Knock-Out
Disease Relevance: Parkinson's Disease
Strain Name: N/A
Genetic Background: Inbred 129/SvEvTac background.
These mice were generated by partially deleting the Snca gene. Homozygous knockout mice are viable and appear to live a normal lifespan. They have no gross morphological or behavioral abnormalities, however, they do exhibit abnormalities in synaptic morphology and function, along with fairly subtle behavioral changes. Over the years, these KO mice have been bred to a variety of other mouse lines, including those expressing human α-synuclein, such as PAC-Tg(SNCAWT) and PAC-Tg(SNCAA53T), as well as MitoPark mice, which have disrupted mitochondria (Ekstrand et el., 2007).
Alpha-synuclein RNA and protein were undetectable in homozygous α-synuclein KO mice. The brain appears largely normal; however, electron microscopy showed a reduced number of synaptic vesicles in hippocampal neurons. Notably, the reserve pool was about 50 percent smaller in KO neurons compared with wild-type. There were no differences in levels of a battery of synaptic proteins including synapsin, synaptophysin, and SNAP-25 (Cabin et al., 2002).
In an electrophysiological assay involving stimulation of Schaffer collaterals, basal synaptic transmission in α-synuclein KO mice was intact. Similarly there was no difference in paired pulse facilitation (PPF), a form of short-term hippocampal plasticity, compared with wild-type mice. KO mice also had a similar response to a high-frequency stimulation, suggesting a comparable number of docked vesicles. However, consistent with EM data, the response to prolonged repetitive stimulation indicated a smaller reserve pool of synaptic vesicles in KO mice. Impaired replenishment of the readily releasable pool of vesicles led to more pronounced synaptic depression in KO neurons (Cabin et al., 2002).
Behaviorally, α-synuclein KO mice appear largely normal. They display normal reflexes and sensory abilities. They performed similarly to controls in most assays of motor function (e.g., Rotarod, distance travelled in open-field test); however, they reared on hind legs less frequently than wild-type controls. They also spent less time in the center of the field, indicating a possible anxiety-like phenotype.
Learning and memory appears intact. At six to 10 months of age, α-synuclein KO mice performed as well as wild-type controls on the Morris water maze, suggesting normal spatial memory. Likewise, contextual memory was intact as measured by their freezing response in tests of conditioned fear (Cabin et al., 2002).
There were no differences between α-synuclein KO mice and wild-type controls in terms of amphetamine-induced locomotor activity (Cabin et al., 2002).
Snca deletion impacted lipid composition of the brain. Alpha-synuclein KO mice had reduced levels of the mitochondrial phospholipid cardiolipin and also reduced levels of phosphatidylglycerol (Ellis et al., 2005; Barceló-Coblijn et al., 2007). The amount of mitochondrial DNA relative to the amount of nuclear DNA did not differ between KO and wild-type brains, suggesting comparable amounts of mitochondria. However, evidence of mitochondrial abnormalities were observed in the form of reduced activity of complex I/III of the electron transport chain (Ellis et al., 2005).
Microglia cultured from α-synuclein KO brains look and act different than wild-type microglia. Notably, KO microglia have a more reactive phenotype (i.e., more ramified). They also have more vacuole-like structures. They exhibit a heightened response to lipopolysaccharide stimulation and secrete elevated levels of pro-inflammatory cytokines, such as TNF-α and interleukin-6. In culture, their phagocytic ability is impaired (Austin et al., 2006).
The mouse Snca gene was disrupted using a targeting vector that replaced exons 4 and 5 with the neomycin resistance gene.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Cognitive Dysfunction
- Dopamine Deficiency
- α-synuclein Inclusions
- Neuronal Loss
Microglia cultured from Snca KO brain were more reactive, ramified. They had vacuole-like structures. Snca KO microglia exhibited exacerbated response to LPS, with greater secretion of pro-inflammatory cytokines.
A possible modest reduction in striatal dopamine level, but highly variable from mouse to mouse.
Motor function was largely intact. Normal performance on the Rotarod and in total distance travelled in the open field test. Subtle differences only (e.g., less rearing behavior than controls). They also spent less time in the center of the field, suggesting a possible anxiety-related phenotype.
Mitochondrial abnormalities include reduced levels of the mitochondrial phospholipid cardiolipin and reduced activity of electron transport chain complex I/III.
Learning and memory appeared intact at 6-10 months of age, based on performance in the Morris water maze and in tests of conditioned fear memory.
No gross abnormalities in the brain.
- Ekstrand MI, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, Thams S, Bergstrand A, Hansson FS, Trifunovic A, Hoffer B, Cullheim S, Mohammed AH, Olson L, Larsson NG. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1325-30. PubMed.
- Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci. 2002 Oct 15;22(20):8797-807. PubMed.
- Ellis CE, Murphy EJ, Mitchell DC, Golovko MY, Scaglia F, Barceló-Coblijn GC, Nussbaum RL. Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking alpha-synuclein. Mol Cell Biol. 2005 Nov;25(22):10190-201. PubMed.
- Barceló-Coblijn G, Golovko MY, Weinhofer I, Berger J, Murphy EJ. Brain neutral lipids mass is increased in alpha-synuclein gene-ablated mice. J Neurochem. 2007 Apr;101(1):132-41. Epub 2007 Jan 23 PubMed.
- Austin SA, Floden AM, Murphy EJ, Combs CK. Alpha-synuclein expression modulates microglial activation phenotype. J Neurosci. 2006 Oct 11;26(41):10558-63. PubMed.