Modification: LRRK2: Knock-In
Disease Relevance: Parkinson's Disease
Strain Name: C57BL/6-Lrrk2tm4.1Arte
Genetic Background: C57BL/6NTac
Availability: Available through Taconic, Cat#13940, Live.
This constitutive knock-in mouse model was generated by introducing the LRRK2 G2019S point mutation into exon 41 of the mouse LRRK2 gene (Matikainen-Ankney et al., 2016). Homozygous mutant mice appear grossly normal. They generate litters comparable in size to wild-type animals, and grow at a normal rate.
LRRK2 levels in both striatal and whole-brain lysates is similar to those of wild-type controls. The cytoarchitecture of the neocortex and striatum appears normal in Nissl-stained brain sections, and striatal levels of tyrosine hydroxylase is similar to those of controls in 3- to 4-month-old animals.
The motor phenotype of these mutants also appears to be essentially normal. Assessments of grip strength, basal and stimulant-induced locomotor activity, as well as performance on the pole test, balance beam, and static rods, revealed no motor impairments in mutant mice at 3-4, 12-13, or 18-19 months of age (Pioli et al., 2011). Consistent with these findings, no alterations in locomotion were detected in 3- to 4-month-old males, as assessed by time spent exploring an arena and average distance covered (Matikainen-Ankney et al., 2016). Moreover, mutant mice’s latency to fall off an accelerating rotarod was similar to that of wild-type animals at 3-4, as well as 14-16, months of age (Pioli et al., 2011; Matikainen-Ankney et al., 2018).
Mutant mice performed similarly to wild-type mice in other behavioral tests as well (Pioli et al., 2011). They showed no deficits in willingness to explore new environments, as assessed by the spontaneous alternation in the Y-maze, and their arousal and attention levels were normal, as assessed by a psycho-vigilance task. Moreover, mutant mice scored similarly to wild-type mice in SHIRPA, a standardized set of tests that assess muscular, cerebellar, sensory and neuropsychiatric function.
However, some behavioral and electrophysiological alterations have been reported. At 18 months, an increased locomotor response after amphetamine challenge was observed (Pioli et al., 2011). In addition, although baseline sociability appeared normal, young adult males (3-4 months old) were unusually resilient to a depression-like syndrome resulting from chronic social stress (Matikainen-Ankney et al., 2018). This lack of behavioral plasticity correlated with abnormal synaptic plasticity in the striatum. When subjected to a stimulation protocol that induces long-term potentiation in spiny projection neurons of the dorsomedial striatum in wild-type mice, D1 (dopamine receptor)-expressing neurons of knock-in mice failed to produce potentiated responses, while D2-expresssing neurons developed long-term depression instead of potentiation.
Moreover, the average amplitude of spontaneous excitatory post-synaptic currents (sEPSCs) was reduced in spiny neurons of the nucleus accumbens (NA), a region in the ventral striatum. A disruption in glutamate AMPA receptor function may contribute to these abnormalities. Mutant NA spiny neurons were largely insensitive to an antagonist of calcium-permeable AMPA receptors, and after exposure to chronic social stress, they failed to generate inward-rectifying AMPA responses characteristic of normal mice. Although details are unavailable, abnormalities in striatal function have also been reported at 18 months of age (Pioli et al., 2011).
In addition, synaptic alterations have been observed during development (Matikainen-Ankney et al., 2016). As assessed by whole-cell patch-clamp recording in brain slices, a fourfold increase in the frequency of spontaneous excitatory post-synaptic currents (sESPCs) produced by spiny projection neurons in the dorsal striatum was detected at post-natal day 21, shortly after a burst in corticostriatal synaptogenesis normally occurs. The findings applied to spiny neurons in both the direct and indirect pathways. They also applied to both heterozygous and homozygous mice, consistent with G2019S being autosomal dominant.
By postnatal day 60, however, sEPSC frequencies returned to levels similar to those of controls. The temporary elevation appears to be caused by enhanced LRRK2 kinase activity since it was abolished by a LRRK2 kinase inhibitor and the elevation was absent from mice carrying LRRK2 D2017A, a mutation that abrogates LRRK2’s kinase activity. When the striatum was surgically isolated from cortical input in G2019S KI mouse brain slices, sEPSC frequency dropped to wild-type levels, suggesting elevated corticostriatal activity importantly contributes to the alteration. Although no changes in synapse density or dendritic spine numbers were detected, spine heads were found to be larger in mutant spiny neurons. Consistently, there was an increase in the probability of larger current amplitudes.
Homologous recombination was used to introduce a mutation corresponding to human G2019S in exon 41 of the mouse LRRK2 gene (Matikainen-Ankney et al., 2016).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Dopamine Deficiency
- α-synuclein Inclusions
- Mitochondrial Abnormalities
The cytoarchitecture of the neocortex and striatum appeared normal in Nissl-stained brain sections of 3-4 month-old mice, and striatal levels of tyrosine hydroxylase were similar to those of controls.
A battery of motor tests revealed no baseline deficits at 3-4, 12-13, and 18-19 months. However, an increased locomotor response after amphetamine challenge was observed at 18 months.
Young adult males (3-4 months old) are unusually resilient to a depression-like syndrome resulting from chronic social stress. Alterations in striatal synaptic plasticity correlate with the phenotype.
Last Updated: 12 Aug 2019
- Matikainen-Ankney BA, Kezunovic N, Mesias RE, Tian Y, Williams FM, Huntley GW, Benson DL. Altered Development of Synapse Structure and Function in Striatum Caused by Parkinson's Disease-Linked LRRK2-G2019S Mutation. J Neurosci. 2016 Jul 6;36(27):7128-41. PubMed.
- Pioli E, Murray TK, Buckner N, Cooper J, Mitchell SN, O'Neill MJ. Behavioral Phenotyping of G2019S Knock-In Leucine-Rich Repeat Kinase 2 (LRRK2) Transgenic Mice. Poster Presentation in 10th International Conference AD/PD, Barcelona, March 2011. Neurodegenerative Dis. Vol. 8, Suppl. 1, 2011.
- Matikainen-Ankney BA, Kezunovic N, Menard C, Flanigan ME, Zhong Y, Russo SJ, Benson DL, Huntley GW. Parkinson's Disease-Linked LRRK2-G2019S Mutation Alters Synaptic Plasticity and Promotes Resilience to Chronic Social Stress in Young Adulthood. J Neurosci. 2018 Nov 7;38(45):9700-9711. Epub 2018 Sep 24 PubMed.
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