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Excessive D1 Dopamine Receptor Activation in the Dorsal Striatum Promotes Autistic-Like Behaviors

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Abstract

The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.

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Acknowledgements

This research was supported by a grant (HI15C1834) from the Ministry of Health and Welfare, Republic of Korea.

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Authors and Affiliations

  1. Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea

    Yunjin Lee, Hannah Kim, Ji-Eun Kim, Jin-Young Park, Juli Choi, Jung-Eun Lee, Eun-Hwa Lee & Pyung-Lim Han

  2. Brain Disease Research Institute, Ewha Womans University, Seoul, Republic of Korea

    Pyung-Lim Han

  3. Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea

    Pyung-Lim Han

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  1. Yunjin Lee
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Electronic supplementary material

Supplementary Figure S1

Reciprocal social interactions of mice with DAT inhibition in SN neurons. a–c Experimental design illustrating assessments of habituation and following reciprocal social interactions (a). The amount of time engaged in facial sniffs (b) and anogenital sniffs (c) by mice injected with DAT-siRNA or control-siRNA is presented. Data are presented in box plots. * and ** denote the differences between the indicated groups at p < 0.05 and p < 0.01, respectively (Student’s t-test). (GIF 17 kb)

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Supplementary Figure S2

Administration of SCH23390 in mice with DAT inhibition in SN neurons blocked autistic-like behaviors. a Experimental design and the time line for DAT-siRNA injection into the SN, administration of SCH23390 (0.02 mg/kg, i.p.) and following behavioral tests. b, c Representative tracks showing exploratory activity of mice injected with DAT-siRNA after SCH23390 or vehicle injection in the three chamber tests that aimed to measure sociability on choices between a social target and an empty cage (b), and social novelty exploration on choices between an earlier stranger (stranger 1) and a new stranger (stranger 2) (c). The amount of time the subject mouse spent in each chamber is presented. n = 9–12 animals. d–f Rearing (d), grooming (e), and digging (f) behavior of mice with DAT-siRNA injection and SCH23390 treatment. n = 8 animals, each. g, h Western blots showing ERK1/2, p-ERK1/2, CaMKIIα, p-CaMKIIα levels in the dorsal striatum of mice injected with DAT-siRNA after SCH23390 or vehicle injection (g). Quantification of Western blots (h). n = 6–8 animals, 3–4 repeats. Data are presented as mean ± SEM or box plots. * and ** denote the differences between the indicated groups at p < 0.05 and p < 0.01, respectively (Student’s t-test, two-way ANOVA, and Holm-Sidak post hoc test). (GIF 57 kb)

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Supplementary Figure S3

Optogenetic stimulation of the nigro-striatal circuit increases p-ERK1/2 and p-CaMKIIα levels in the dorsal striatum and induces repetitive behaviors. a Experimental design for optic stimulation of the nigro-striatal circuit (blue), repetitive behavior tests and following tissue sample preparation. Blue light (473 nm, at 20 Hz with a 30-ms spike width and a 3–3.5-mW light intensity) was administered for 5 min, as indicated. Tissue samples were prepared 60 min after optic stimulation (purple arrow). All examined animals had been used in the sociability tests (behavioral tests(a)), but had been in their home cages for more than 7 days prior to this experiment. A diagram illustrating the injection of viral vectors into the SN (green arrow) and optic stimulation of the nigro-striatal circuit through a fiber-optic (blue) (left panel). b, c Photomicrographs showing p-ERK1/2 and p-CaMKIIα expressions in the dorsal striatum of mice carrying AAV-CON (AAV-CON) or AAV-ChR2 (AAV-ChR2) following optic stimulation of the nigro-striatal circuit (b). Expression levels of p-ERK1/2- and p-CaMKIIα-positive cells were normalized to the control (c). Scale bars, 50 μm. n = 4 animals, each. d–f Rearing (d), grooming (e), and digging (f) of mice carrying AAV-ChR2 (AAV-ChR2) before (Off) and after (On) optic stimulation of the nigro-striatal circuit. n = 4 animals. Data are presented as mean ± SEM or box plots. * denotes the difference between the indicated groups at p < 0.05 (Student’s t-test). (GIF 71 kb)

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Supplementary Figure S4

Administration of SKF38393 in normal mice induces autistic-like behaviors. a Experimental design for SKF38393 injection in normal mice, and following behavioral tests. b–d Representative tracks showing exploratory activity for sociability (b), social novelty exploration (c), and social preference (d) of normal mice treated with vehicle (Veh) or SKF38393 in the three-chamber test. The amount of time spent in each chamber is presented. n = 8–12 animals. e, f Reciprocal social interactions. The amount of time for facial sniff (e) and anogenital sniff (f) of mice treated with vehicle (Veh) or SKF38393 is presented. n = 9–10 animals. g–j Grooming (g), rearing (h), digging (i), and marble-burying (j) behaviors of mice injected with vehicle (Veh) or SKF38393 placed in a new cage. ** in Fig. S4j denotes the difference between vehicle and SKF38393 at p < 0.01 at the time points marked by arrowheads. n = 8–10. k, l Western blots showing p-ERK1/2, p-CaMKIIα, p-CREB, and p-GluN2B (S1303) levels in the dorsal striatum of mice injected with vehicle (Veh) or SKF38393 (k). Tissue samples were prepared 1 h after SKF38393 or vehicle injection. Quantification of Western blots (l). n = 4–6 animals, 4 repeats. Data are presented as mean ± SEM or box plots. * and ** denote the differences between the indicated groups at p < 0.05 and p < 0.01, respectively (Student’s t-test, two-way repeated measures ANOVA, two-way ANOVA, and Holm-Sidak post hoc test). (GIF 75 kb)

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Supplementary Figure S5

D2 KO mice exhibit deficits in social behaviors and repetitive behaviors. a, b Representative tracks showing exploratory activity for social novelty exploration (a) and social preference (b) of WT and D2 KO mice in the three-chamber test. The amount of time the subject mouse spent in each chamber is presented. n = 10–19 animals. c, d Representative tracks showing exploratory activity for sociability (c) and social preference (d) of WT and D2 KO mice in the U-field assay. The amount of time the subject mouse spent in each field is presented. n = 9–10 animals. e–h Grooming (e), rearing (f), digging (g), and marble-burying behaviors (h) of WT and D2 KO mice when placed individually in a new cage. n = 9–12. i, j No sex difference in sociability (i) and social novelty exploration (j) of male and female D2 KO mice in the three-chamber test. The amount of time the subject mouse spent in each chamber is presented. n = 10 animals each. k–m No sex difference in grooming (k), rearing (l), and digging (m) of male and female D2 KO mice in a new cage. n = 7–8. n Olfactory habituation and dishabituation assays of WT and D2 KO mice. The amount of time of WT and D2 KO mice spent sniffing the cotton tip is presented. n = 6 animals each. Data are presented as mean ± SEM or box plots. * and ** denote the differences between the indicated groups at p < 0.05 and p < 0.01, respectively (Student’s t-test, two-way ANOVA, two-way repeated measures ANOVA, and Holm-Sidak post hoc test). For (n), * and ** denote the difference between previous odorant and indicated new odorant at p < 0.05 and p < 0.01. ## denotes the main effect of repeated treatment in indicated groups at p < 0.01 (two-way repeated measures ANOVA and Holm-Sidak post hoc test). (GIF 91 kb)

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Supplementary Figure S6

Heterozygous D2 KO mice exhibit autistic-like behaviors following weak activation of D1 receptors. a, b Representative tracks showing exploratory activity for sociability (a) and social novelty exploration (b) of WT and heterozygous D1 KO mice (D1+/−) in the three chamber test. The amount of time the subject mouse spent in each chamber is presented. n = 11–13 animals each. c–e Grooming (c), rearing (d), and digging (e) of WT and heterozygous D1 KO mice placed in a new cage. n = 10–17. f, g Exploratory activity for sociability (f) and social novelty exploration (g) of WT and heterozygous D2 KO mice (D2+/−) in the three-chamber test. The amount of time the subject mouse spent in each chamber is presented. n = 10–11 animals each. h–j Grooming (h), rearing (i), and digging (j) of WT and heterozygous D2 KO mice placed in a new cage. n = 9–10. k, l Exploratory activity for sociability (k) and social novelty exploration (l) of WT and heterozygous D2 KO mice in the three-chamber test following SKF38393 treatment. The amount of time the subject mouse spent in each chamber is presented. Behaviors were examined 30 min after SKF38393 (0.5 mg/Kg, i.p.) injection. n = 7–8 animals. m–o Grooming (m), rearing (n), and digging (o) of WT and heterozygous D2 KO mice in a new cage 30 min after SKF38393 (0.5 mg/kg, i.p.) injection. n = 7–9 animals. Data are presented box plots. * and ** denote the differences between the indicated groups at p < 0.05 and p < 0.01, respectively (Student’s t-test, two-way ANOVA, and Holm-Sidak post hoc test). (GIF 82 kb)

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Supplementary Figure S7

Analysis of physiological effects of increased p-CaMKIIα and p-ERK1/2, and transcript levels of synaptic proteins in the dorsal striatum of D2 KO mice. a Experimental design for CaMKIIα-siRNA or ERK2-siRNA injection in the dorsal striatum of D2 KO mice and following behavioral tests. b–e Sociability (b), grooming (c), rearing (d), and digging (e) of D2 KO mice with siRNA-mediated inhibition of CaMKIIα or ERK2 in the dorsal striatum. f–h Real-time PCR data showing transcript levels of D1 and D2 dopamine receptors (f), GluA1, GluA2, GluN1, GluN2A, and GluN2B glutamate receptor subunits (g), and the postsynaptic components of PSD93, PSD95, Homer1a, Shank3, and neuroligin 3(Ngn3) (h) in the dorsal striatum of WT and D2 KO mice. n = 6–8 animals, 4–8 repeats. Data are presented as box plots or mean ± SEM. * and ** denote the differences between the indicated groups at p < 0.05 and p < 0.01, respectively (Student’s t-test, one-way ANOVA, two-way ANOVA, and Holm-Sidak post hoc test). (GIF 56 kb)

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Supplementary Figure S8

Analyses of the effective doses of ecopipam and SCH23390 for sociability and motor activity tests. a–g Timeline for drug injection and behavioral tests (a). Sociability (b, d, f) and locomotion (c, e, g) of D2 KO mice injected with ecopipam at the doses of 0.01–0.03 mg/kg. Ecopipam at the doses of 0.02–0.03 mg/kg (d–g), but not at 0.01 mg/kg (b, c), rescued sociability deficits (d, f) in the absence of motor activity suppression (e, g). h–p Sociability (h, j, m, o), locomotion (i, k, n, p) and grooming (l) of AC5 KO mice (h–n) or WT mice (o, p) injected with SCH23390 at the doses of 0.01–0.03 mg/kg. SCH23390 at the dose of 0.03 mg/kg rescued sociability deficits of AC5 KO mice (m) but produced motor activity suppression (n). Administration of SCH23390 (0.02 mg/kg) in WT mice did not change sociability (o) and locomotion (p). Data are presented as box plots (n = 6–8). * and ** denote the differences between the indicated groups at p < 0.05 and p < 0.01, respectively (Student’s t-test, two-way ANOVA, and Holm-Sidak post hoc test). (GIF 59 kb)

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Lee, Y., Kim, H., Kim, JE. et al. Excessive D1 Dopamine Receptor Activation in the Dorsal Striatum Promotes Autistic-Like Behaviors. Mol Neurobiol 55, 5658–5671 (2018). https://doi.org/10.1007/s12035-017-0770-5

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