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Updated: Mar 2, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Human LRRK2 G2019S mutation represses post-synaptic protein PSD95 and causes cognitive impairment in transgenic mice
Samuel O Adeosun1, Xu Hou1, Baoying Zheng1
1Department of Pathology, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216, United States.
Background:
LRRK2 G2019S mutation is associated with increased kinase activity and is the most common mutation associated with late-onset PD. However, the transgenic mouse model has not recapitulated cardinal PD-related motor phenotypes. Non-motor symptoms of PD including cognitive impairments are very common and may appear earlier than the motor symptoms. The objective of this study was to determine whether human LRRK2 with G2019S mutation causes hippocampus-dependent cognitive deficits in mice.
Results:
Male (LRRK2-G2019S) LRRK2-Tg mice showed impairments in the early portion of the Two-day radial arm water maze acquisition trial as well as in the reversal learning on the third day. However, their performance was similar to Non-Tg controls in the probe trial. LRRK2-Tg mice also displayed impairments in the novel arm discrimination test but not in the spontaneous alternation test in Y-maze. Interestingly, there was no statistically significant locomotor impairment during any of these cognitive test, nor in the locomotor tests including open field, accelerating rotarod and pole tests. Expression of the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin was lower in hippocampal homogenates of LRRK2-Tg mice.
Conclusion:
Consistent with previous reports in human LRRK2 G2019S carriers, the current data suggests that cognitive dysfunctions are present in LRRK2-Tg mice even in the absence of locomotor impairment. LRRK2 G2019S mutation represses the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin. This study also suggests that mild cognitive impairment may appear earlier than motor dysfunctions in LRRK2-G2019S mutation carriers.
Insights
The LRRK2 G2019S mutation causes cognitive deficits in mice, even without motor symptoms. This suggests early cognitive impairment may precede motor dysfunction in Parkinson's disease.
Area of Science:
- Neuroscience
- Genetics
- Parkinson's Disease Research
Background:
- The LRRK2 G2019S mutation is linked to Parkinson's disease (PD) but existing mouse models fail to show motor deficits.
- Non-motor symptoms, including cognitive impairment, are prevalent in PD and can manifest early.
Purpose of the Study:
- To investigate if the human LRRK2 G2019S mutation induces hippocampus-dependent cognitive deficits in mice.
- To explore the relationship between LRRK2 G2019S mutation, cognitive function, and motor phenotypes.
Main Methods:
- Utilized LRRK2-G2019S transgenic (LRRK2-Tg) mice and non-transgenic (Non-Tg) controls.
- Assessed cognitive function using the radial arm water maze and Y-maze spontaneous alternation test.
- Evaluated motor function through open field, accelerating rotarod, and pole tests.
- Analyzed hippocampal protein expression of PSD-95 and synaptophysin.
Main Results:
- LRRK2-Tg mice exhibited deficits in spatial learning and reversal learning but not in probe trials or spontaneous alternation.
- No significant motor impairments were observed in LRRK2-Tg mice across various tests.
- Reduced expression of postsynaptic protein PSD-95, but not presynaptic synaptophysin, was found in the hippocampi of LRRK2-Tg mice.
Conclusions:
- The LRRK2 G2019S mutation leads to cognitive dysfunction in mice, independent of motor deficits.
- The mutation impacts postsynaptic protein PSD-95 levels in the hippocampus.
- Cognitive impairment may precede motor symptoms in individuals with the LRRK2 G2019S mutation.
