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R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations

Xenias, Harry S., Chen, Chuyu, Kang, Shuo, Cherian, Suraj, Situ, Xiaolei, Shanmugasundaram, Bharanidharan, Liu, Guoxiang, Scesa, Giuseppe, Chan, C. Savio, Parisiadou, Loukia·2022·Communications Biology
DOI 10.1038/s42003-022-04136-8PMC PMC9649688

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Abstract

LRRK2 mutations are closely associated with Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how LRRK2 mutations altered striatal physiology. While we found that both R1441C and G2019S mice displayed reduced nigrostriatal dopamine release, hypoexcitability in indirect-pathway striatal projection neurons, and alterations associated with an impaired striatal-dependent motor learning were observed only in the R1441C mice. We also showed that increased synaptic PKA activities in the R1441C and not G2019S mice underlie the specific alterations in motor learning deficits in the R1441C mice. In summary, our data argue that LRRK2 mutations’ impact on the striatum cannot be simply generalized. Instead, alterations in electrochemical, electrophysiological, molecular, and behavioral levels were distinct between LRRK2 mutations. Our findings offer mechanistic insights for devising and optimizing treatment strategies for PD patients.

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Fig. 1 RC and GS LRRK2 mice have decreased nigrostriatal dopamine release. a A schematic diagram of LRRK2 protein: a family of Ras-like G-proteins with functionally distinct multi-domains, consisting of armadillo repeats (ARM), ankyrin repeats (ANK), the leucine-rich repeats (LRR), the C-terminal of Roc (COR), the ROC GTPase domain where the R1441C/G/H (RC) mutations reside, and the kinase domain where the G2019S (GS) mutation resides. The WD40 domain is involved in membrane binding with ARM and ANK believed to stabilize the electrostatic surfaces of the domains. b. Brightfield photomicrograph of a parasagittal slice with a concentric stimulating electrode placed in the dorsal striatum (dStr); a carbon fiber electrode was inserted adjacent to the stimulation site. Ctx, cortex. c Population data showing for evoked [DA] in WT, RC, and GS LRRK2 KI mice. The median evoked concentrations were: [DA]WT = 1057.6 ± 117.9 nM (n = 10); [DA]RC = 538.7 ± 143.2 nM (n = 9); [DA]GS = 554.9 ± 218.4 nM (n = 13). Compared to WT mice, evoked dopamine [DA] was decreased in RC mice (p = 0.006, Mann–Whitney U test). Similarly, compared to WT mice, [DA] was less in GS mice (p = 0.001; Mann–Whitney U test). There was no difference in evoked release between RC and GS mice (p = 0.69; Mann–Whitney U test). d Representative time courses for [DA] with corresponding cyclic voltammograms and color maps of fast-scanning cyclic voltammetry recordings. Peak evoked responses: [DA]WT = 1223.7 nM; [DA]RC = 655.1 nM; [DA]GS = 710.4 nM. Colormaps are normalized to the oxidation current from the WT recording. ** denotes p < 0.01. See Supplementary Table 1 for complete sample sizes by sex and statistical results.
Fig. 1 RC and GS LRRK2 mice have decreased nigrostriatal dopamine release. a A schematic diagram of LRRK2 protein: a family of Ras-like G-proteins with functionally distinct multi-domains, consisting of armadillo repeats (ARM), ankyrin repeats (ANK), the leucine-rich repeats (LRR), the C-terminal of Roc (COR), the ROC GTPase domain where the R1441C/G/H (RC) mutations reside, and the kinase domain where the G2019S (GS) mutation resides. The WD40 domain is involved in membrane binding with ARM and ANK believed to stabilize the electrostatic surfaces of the domains. b. Brightfield photomicrograph of a parasagittal slice with a concentric stimulating electrode placed in the dorsal striatum (dStr); a carbon fiber electrode was inserted adjacent to the stimulation site. Ctx, cortex. c Population data showing for evoked [DA] in WT, RC, and GS LRRK2 KI mice. The median evoked concentrations were: [DA]WT = 1057.6 ± 117.9 nM (n = 10); [DA]RC = 538.7 ± 143.2 nM (n = 9); [DA]GS = 554.9 ± 218.4 nM (n = 13). Compared to WT mice, evoked dopamine [DA] was decreased in RC mice (p = 0.006, Mann–Whitney U test). Similarly, compared to WT mice, [DA] was less in GS mice (p = 0.001; Mann–Whitney U test). There was no difference in evoked release between RC and GS mice (p = 0.69; Mann–Whitney U test). d Representative time courses for [DA] with corresponding cyclic voltammograms and color maps of fast-scanning cyclic voltammetry recordings. Peak evoked responses: [DA]WT = 1223.7 nM; [DA]RC = 655.1 nM; [DA]GS = 710.4 nM. Colormaps are normalized to the oxidation current from the WT recording. ** denotes p < 0.01. See Supplementary Table 1 for complete sample sizes by sex and statistical results.CC BY · PubMed Central
Fig. 2 iSPNs in RC LRRK2 mice have decreased excitability. a, b Representative whole-cell current-clamp recordings of dSPNs and iSPNs in WT and RC LRRK2 KI mice. The three injection steps shown represent the currents for the different voltage responses, the hyperpolarization response, the first occurrence of action potentials, and the maximum firing, respectively. No differences in the frequency-current (F-I) function were found for dSPNs between WT and RC mice at the current where the half-maximum firing occurred in the population data (I = 475 pA, spikesWT = 12.0 ± 4.0, n = 20 cells; spikesRC = 14.0 ± 3.0, n = 30 cells; p = 0.21, Mann–Whitney U test). For iSPNs there was a decrease of the firing response to half-maximum firing current in the RC mice compared to the WT mice (I = 325 pA, spikesWT = 14.0 ± 5.0, n = 20 cells; spikesRC = 6.0 ± 6.0, n = 23 cells; p = 0.037, Mann–Whitney U test). The current where the maximal difference between the F-I functions for the WT and RC mice was also calculated (I = 625 pA, dotted line) to compare the number of elicited spikes between the WT and RC mice. We found a decrease in the number of spikes elicited in RC mice compared to WT mice (spikesWT = 22.0 ± 4.5, n = 17 cells; spikesRC = 15.0 ± 5.0, n = 23 cells; p = 0.0011, Mann–Whitney U test). c, d Representative whole-cell current-clamp recordings of dSPNs and iSPNs in WT and GS LRRK2 KI mice with population F-I data. For GS mice, no differences were found in the half-maximum firing responses for either dSPNs (spikesWT = 8.0 ± 5.0, n = 13 cells; spikesGS = 11.0 ± 3.0, n = 29 cells; p = 0.12, Mann–Whitney U test) or iSPNs (spikesWT = 10.5 ± 4.8, n = 20 cells; spikesGS = 12.0 ± 4.0, n = 28 cells; p = 0.73, Mann–Whitney U test). F-I data are shown as mean ± standard error of the mean. * denotes p < 0.05. See Supplementary Table 2 for complete sample sizes and statistical results.
Fig. 2 iSPNs in RC LRRK2 mice have decreased excitability. a, b Representative whole-cell current-clamp recordings of dSPNs and iSPNs in WT and RC LRRK2 KI mice. The three injection steps shown represent the currents for the different voltage responses, the hyperpolarization response, the first occurrence of action potentials, and the maximum firing, respectively. No differences in the frequency-current (F-I) function were found for dSPNs between WT and RC mice at the current where the half-maximum firing occurred in the population data (I = 475 pA, spikesWT = 12.0 ± 4.0, n = 20 cells; spikesRC = 14.0 ± 3.0, n = 30 cells; p = 0.21, Mann–Whitney U test). For iSPNs there was a decrease of the firing response to half-maximum firing current in the RC mice compared to the WT mice (I = 325 pA, spikesWT = 14.0 ± 5.0, n = 20 cells; spikesRC = 6.0 ± 6.0, n = 23 cells; p = 0.037, Mann–Whitney U test). The current where the maximal difference between the F-I functions for the WT and RC mice was also calculated (I = 625 pA, dotted line) to compare the number of elicited spikes between the WT and RC mice. We found a decrease in the number of spikes elicited in RC mice compared to WT mice (spikesWT = 22.0 ± 4.5, n = 17 cells; spikesRC = 15.0 ± 5.0, n = 23 cells; p = 0.0011, Mann–Whitney U test). c, d Representative whole-cell current-clamp recordings of dSPNs and iSPNs in WT and GS LRRK2 KI mice with population F-I data. For GS mice, no differences were found in the half-maximum firing responses for either dSPNs (spikesWT = 8.0 ± 5.0, n = 13 cells; spikesGS = 11.0 ± 3.0, n = 29 cells; p = 0.12, Mann–Whitney U test) or iSPNs (spikesWT = 10.5 ± 4.8, n = 20 cells; spikesGS = 12.0 ± 4.0, n = 28 cells; p = 0.73, Mann–Whitney U test). F-I data are shown as mean ± standard error of the mean. * denotes p < 0.05. See Supplementary Table 2 for complete sample sizes and statistical results.CC BY · PubMed Central
Fig. 3 RC KI mice show dopamine-dependent motor learning impairments. a Schematic of the rotarod training paradigm. Mice were assessed over a total of 18 daily sessions, where every daily session consisted of five trials. WT, GS, and RC mice were administered either saline or a cocktail of D1 receptor (SCH23390) and D2 receptor (eticlopride), 1 mg/kg of each antagonist 30 min prior to daily sessions, and trained for five successive days in an accelerated rotarod. After a 72 h break, the mice were returned to the rotarod for an additional 13 days of a drug-free recovery phase. b Genotype-dependent effect of blocking both D1 and D2 receptors during the first five sessions on rotarod performance of WT, RC, and GS mice. The average latency in the early (session 6–8) and late (session 16–18) stages in the drug-free recovery phase in b is summarized in c. Open and filled bars represent the average performance of saline control and drug-treated mice, respectively (saline treated groups: nWT = 10 mice, nRC = 10 mice, and nGS = 9 mice; D1 + D2 receptor antagonist treated groups: nWT = 13 mice, nRC = 11 mice, and nGS = 11 mice; ***p < 0.001 vs genotype-matched saline control). d Improved performance of RC mice (n = 10) received antagonist cocktail but no training during the first five sessions. The RCD1+D2 group data is from Fig. 3b–c for reference. See Supplementary Table 7 for complete sample sizes and statistical results. e. Distance traveled in the open field after five days of rotarod training with either vehicle or dopamine receptor antagonist cocktail treatment. Another group of mice received dopamine antagonist treatment and rotarod training for five days under the same schedule described in a-c and were tested in the open field immediately after the 72-hr break instead of the drug-free phase (saline treated groups: nWT = 11 mice, nRC = 8, and nGS = 7 mice; D1R + D2R antagonist treated groups: nWT = 7, nRC = 5, and nGS = 6 mice; D1R antagonist treated groups: nWT = 7, nRC = 8, and nGS = 9 mice; D2R antagonist treated groups: nWT = 8, nRC = 11, and nGS = 7 mice).
Fig. 3 RC KI mice show dopamine-dependent motor learning impairments. a Schematic of the rotarod training paradigm. Mice were assessed over a total of 18 daily sessions, where every daily session consisted of five trials. WT, GS, and RC mice were administered either saline or a cocktail of D1 receptor (SCH23390) and D2 receptor (eticlopride), 1 mg/kg of each antagonist 30 min prior to daily sessions, and trained for five successive days in an accelerated rotarod. After a 72 h break, the mice were returned to the rotarod for an additional 13 days of a drug-free recovery phase. b Genotype-dependent effect of blocking both D1 and D2 receptors during the first five sessions on rotarod performance of WT, RC, and GS mice. The average latency in the early (session 6–8) and late (session 16–18) stages in the drug-free recovery phase in b is summarized in c. Open and filled bars represent the average performance of saline control and drug-treated mice, respectively (saline treated groups: nWT = 10 mice, nRC = 10 mice, and nGS = 9 mice; D1 + D2 receptor antagonist treated groups: nWT = 13 mice, nRC = 11 mice, and nGS = 11 mice; ***p < 0.001 vs genotype-matched saline control). d Improved performance of RC mice (n = 10) received antagonist cocktail but no training during the first five sessions. The RCD1+D2 group data is from Fig. 3b–c for reference. See Supplementary Table 7 for complete sample sizes and statistical results. e. Distance traveled in the open field after five days of rotarod training with either vehicle or dopamine receptor antagonist cocktail treatment. Another group of mice received dopamine antagonist treatment and rotarod training for five days under the same schedule described in a-c and were tested in the open field immediately after the 72-hr break instead of the drug-free phase (saline treated groups: nWT = 11 mice, nRC = 8, and nGS = 7 mice; D1R + D2R antagonist treated groups: nWT = 7, nRC = 5, and nGS = 6 mice; D1R antagonist treated groups: nWT = 7, nRC = 8, and nGS = 9 mice; D2R antagonist treated groups: nWT = 8, nRC = 11, and nGS = 7 mice).CC BY · PubMed Central
Fig. 4 Synaptic PKA signaling is increased in the striatum of RC mice trained in the rotarod task. a Workflow of proteomic screening for total TMT-labeled peptides in WT, RC, and GS striatal crude synaptosomal fraction after 5 days of cocktail (D1R and D2R antagonists) administration and rotarod training. b Pairwise comparisons of WT vs. RC and WT vs. GS proteins revealed that 90 proteins for WT vs. RC and 162 proteins for WT vs. GS were differentially regulated. These findings were further quantified if the proteins were up- or down-regulated. c Venn diagrams show the overlap of modulated (both up and down-regulated) proteins between WT versus RC and WT versus GS comparisons. 66 differentially regulated proteins were common between the WT vs. RC and WT vs. GS groups. d KEGG analysis of selective pathways altered in RC synaptosomal fraction compared to WT. The top enriched pathways are found in Supplementary Fig. 8, while the full lists of differentially expressed proteins and pathways in WT versus RC and WT versus GS can be found in Supplementary F 1 and 2. e WB analysis of striatal P2 fraction of WT, RC, and GS mice after the rotarod paradigm probed for p-PKA, PSD95, and β-actin. f Quantification of p-PKA band intensities normalized to PSD95. Summary graphs represent the mean, while error bars SEM, *p < 0.05, Tukey post hoc following one-way ANOVA (n = 5). g Western blot analysis of striatal extracts of D1 + D2 receptors antagonists administered WT, RC and RC injected with shPKARIIβ probed for p-PKA substrates. Session 5 refers to the end of the drug phase of the rotarod, whereas session 18 denotes the end of the rotarod behavioral test. h Quantification of p-PKA bands normalized to α-tubulin in striatal extracts of WT and RC mice after session 5 and 18 of the rotarod task described in Fig. 3. Summary graphs reflect the mean, and error bars reflect SEM. *p < 0.05, ****p < 0.0001, Tukey post-hoc test following one-way ANOVA (n = 3).
Fig. 4 Synaptic PKA signaling is increased in the striatum of RC mice trained in the rotarod task. a Workflow of proteomic screening for total TMT-labeled peptides in WT, RC, and GS striatal crude synaptosomal fraction after 5 days of cocktail (D1R and D2R antagonists) administration and rotarod training. b Pairwise comparisons of WT vs. RC and WT vs. GS proteins revealed that 90 proteins for WT vs. RC and 162 proteins for WT vs. GS were differentially regulated. These findings were further quantified if the proteins were up- or down-regulated. c Venn diagrams show the overlap of modulated (both up and down-regulated) proteins between WT versus RC and WT versus GS comparisons. 66 differentially regulated proteins were common between the WT vs. RC and WT vs. GS groups. d KEGG analysis of selective pathways altered in RC synaptosomal fraction compared to WT. The top enriched pathways are found in Supplementary Fig. 8, while the full lists of differentially expressed proteins and pathways in WT versus RC and WT versus GS can be found in Supplementary F 1 and 2. e WB analysis of striatal P2 fraction of WT, RC, and GS mice after the rotarod paradigm probed for p-PKA, PSD95, and β-actin. f Quantification of p-PKA band intensities normalized to PSD95. Summary graphs represent the mean, while error bars SEM, *p < 0.05, Tukey post hoc following one-way ANOVA (n = 5). g Western blot analysis of striatal extracts of D1 + D2 receptors antagonists administered WT, RC and RC injected with shPKARIIβ probed for p-PKA substrates. Session 5 refers to the end of the drug phase of the rotarod, whereas session 18 denotes the end of the rotarod behavioral test. h Quantification of p-PKA bands normalized to α-tubulin in striatal extracts of WT and RC mice after session 5 and 18 of the rotarod task described in Fig. 3. Summary graphs reflect the mean, and error bars reflect SEM. *p < 0.05, ****p < 0.0001, Tukey post-hoc test following one-way ANOVA (n = 3).CC BY · PubMed Central
Fig. 5 PKARIIβ knockdown modifies p-PKA signaling in the striatum of WT and RC mice. a Striatal sections of AAV-eGFP-shcontrol and AAV-eGFP-shPKARIIβ injected WT and RC mice. Scale bar, 50 μm. b Western blot analysis of striatum of WT mice injected with AAV-sh-control and AAV-sh-PKARIIβ viral constructs probed for PKARIIβ. c Quantification of PKARIIβ from b normalized to β-actin. Summary graphs represent the mean, while error bars SEM, **p < 0.01, unpaired t-test (n = 5). d Western Blot analysis of striatum of WT mice injected with, AAV-sh-control and AAV-sh-PKARIIβ probed for PKARIIβ, pPKARIIβ, p-S845GluA1, GluA1 and β-actin. e Western blot analysis of striatal extracts from WT and RC mice injected with AAV-sh-control and AAV-sh-PKARIIβ viral constructs probed for PKARIIβ, and gapdh. f Quantification of PKA bands normalized to gapdh. Summary graphs represent the mean, while error bars SEM, *p < 0.05, **p < 0.01, Tukey post hoc following one-way ANOVA (n = 3).
Fig. 5 PKARIIβ knockdown modifies p-PKA signaling in the striatum of WT and RC mice. a Striatal sections of AAV-eGFP-shcontrol and AAV-eGFP-shPKARIIβ injected WT and RC mice. Scale bar, 50 μm. b Western blot analysis of striatum of WT mice injected with AAV-sh-control and AAV-sh-PKARIIβ viral constructs probed for PKARIIβ. c Quantification of PKARIIβ from b normalized to β-actin. Summary graphs represent the mean, while error bars SEM, **p < 0.01, unpaired t-test (n = 5). d Western Blot analysis of striatum of WT mice injected with, AAV-sh-control and AAV-sh-PKARIIβ probed for PKARIIβ, pPKARIIβ, p-S845GluA1, GluA1 and β-actin. e Western blot analysis of striatal extracts from WT and RC mice injected with AAV-sh-control and AAV-sh-PKARIIβ viral constructs probed for PKARIIβ, and gapdh. f Quantification of PKA bands normalized to gapdh. Summary graphs represent the mean, while error bars SEM, *p < 0.05, **p < 0.01, Tukey post hoc following one-way ANOVA (n = 3).CC BY · PubMed Central
Fig. 6 Aberrant synaptic PKA activities underlie the dopamine-dependent RC impaired motor learning. a Western blot analysis of striatal extracts from WT and RC mice injected with AAV-sh-control and AAV-sh-PKARIIβ viral constructs probed for p-PKA and β-actin. b Quantification of p-PKA bands normalized to β-actin. Summary graphs represent the mean, while error bars SEM, *p < 0.05, ***p < 0.001, Tukey post hoc following one-way ANOVA (n = 3). c, d The latency to fall of RC mice treated with the dopamine receptors antagonists’ cocktail and injected either with control AAV-sh-control and AAV-sh-PKARIIβ viruses was assessed in the rotarod paradigm described in Fig. 3a. A subset of mice was administered saline and used as a reference for the effect of D1 and D2 antagonism (saline treated group nRCsaline = 10, D1 + D2 antagonists treated groups nRCsh-control = 13, and nRC-shPKARIIβ = 10). The average latency in the drug-free recovery phase of the three late sessions (16–18) are summarized in e. Asterisks show statistical significance for Tukey’s multiple comparison tests after two-way ANOVA. d Dopamine receptor antagonists treated WT mice were injected with shPKARIIβ virus, and their latency to fall was assessed in the accelerating test. WT mice administered saline and cocktail are used as reference, saline treated group nWT = 10, D1 + D2 receptor antagonist treated groups nRC = 12, and nRC-shPKARIIβ = 11. The average latency in the three late sessions (16–18) of the rotarod test is shown in f. Asterisks show statistical significance for Tukey’s multiple comparison tests after two-way ANOVA. g Working model of aberrant PKA synaptic activities at a blowup of a spine of an SPN (left). Presynaptic dysregulation of LRRK2 activity in RC and GS mutants has a common disruption of the synaptic vesicle cycle, which leads to decreased dopamine release. In addition, in RC mutants, there is a postsynaptic translocation of PKA into the dendritic spines with aberrant increased PKA activity, which disrupts synaptic signaling and interferes with motor learning and performance (measured by decreased latency to fall off rotarod).
Fig. 6 Aberrant synaptic PKA activities underlie the dopamine-dependent RC impaired motor learning. a Western blot analysis of striatal extracts from WT and RC mice injected with AAV-sh-control and AAV-sh-PKARIIβ viral constructs probed for p-PKA and β-actin. b Quantification of p-PKA bands normalized to β-actin. Summary graphs represent the mean, while error bars SEM, *p < 0.05, ***p < 0.001, Tukey post hoc following one-way ANOVA (n = 3). c, d The latency to fall of RC mice treated with the dopamine receptors antagonists’ cocktail and injected either with control AAV-sh-control and AAV-sh-PKARIIβ viruses was assessed in the rotarod paradigm described in Fig. 3a. A subset of mice was administered saline and used as a reference for the effect of D1 and D2 antagonism (saline treated group nRCsaline = 10, D1 + D2 antagonists treated groups nRCsh-control = 13, and nRC-shPKARIIβ = 10). The average latency in the drug-free recovery phase of the three late sessions (16–18) are summarized in e. Asterisks show statistical significance for Tukey’s multiple comparison tests after two-way ANOVA. d Dopamine receptor antagonists treated WT mice were injected with shPKARIIβ virus, and their latency to fall was assessed in the accelerating test. WT mice administered saline and cocktail are used as reference, saline treated group nWT = 10, D1 + D2 receptor antagonist treated groups nRC = 12, and nRC-shPKARIIβ = 11. The average latency in the three late sessions (16–18) of the rotarod test is shown in f. Asterisks show statistical significance for Tukey’s multiple comparison tests after two-way ANOVA. g Working model of aberrant PKA synaptic activities at a blowup of a spine of an SPN (left). Presynaptic dysregulation of LRRK2 activity in RC and GS mutants has a common disruption of the synaptic vesicle cycle, which leads to decreased dopamine release. In addition, in RC mutants, there is a postsynaptic translocation of PKA into the dendritic spines with aberrant increased PKA activity, which disrupts synaptic signaling and interferes with motor learning and performance (measured by decreased latency to fall off rotarod).CC BY · PubMed Central

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Metadata

Authors
Xenias, H. S., Chen, C., Kang, S., Cherian, S., Situ, X., Shanmugasundaram, B., Liu, G., Scesa, G., Chan, C. S., & Parisiadou, L.
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2022-11-10
Volume
5
Issue
1
ISSN
2399-3642
DOI
10.1038/s42003-022-04136-8
PMC
PMC9649688
Cited by
32
References
8
Language
en
Licence
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (R01 NS097901)
  • Michael J. Fox Foundation for Parkinson’s Research (020600)

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