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Dynamic rewiring of neural circuits in the motor cortex in mouse models of Parkinson's disease

Nature Neuroscience volume 18, pages 1299–1309 (2015)Cite this article

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Abstract

Dynamic adaptations in synaptic plasticity are critical for learning new motor skills and maintaining memory throughout life, which rapidly decline with Parkinson's disease (PD). Plasticity in the motor cortex is important for acquisition and maintenance of motor skills, but how the loss of dopamine in PD leads to disrupted structural and functional plasticity in the motor cortex is not well understood. Here we used mouse models of PD and two-photon imaging to show that dopamine depletion resulted in structural changes in the motor cortex. We further discovered that dopamine D1 and D2 receptor signaling selectively and distinctly regulated these aberrant changes in structural and functional plasticity. Our findings suggest that both D1 and D2 receptor signaling regulate motor cortex plasticity, and loss of dopamine results in atypical synaptic adaptations that may contribute to the impairment of motor performance and motor memory observed in PD.

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Figure 1: Spine turnover is increased in the dendritic spines of layer V pyramidal neurons of M1 in two mouse models of PD.
Figure 2: Spine dynamics in M1 in PD mouse models.
Figure 3: Spine elimination and formation are differentially regulated by different types of dopamine receptors in M1.
Figure 4: Spine elimination and formation are regulated by direct dopaminergic projection to M1.
Figure 5: LTP is impaired following dopamine depletion.
Figure 6: LTD following dopamine depletion.
Figure 7: Spine formation and elimination are separately regulated.
Figure 8: Dopamine depletion impairs motor skill learning and learning-induced spine formation and elimination.

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Acknowledgements

The authors thank H. Bronte-Stewart, L. Chen and members of Ding laboratory for discussions. We also thank S.Q. Zeng, X.H. Lv and the Optical Bioimaging Core Facility of Wuhan National Laboratory for Optoelectronics–Huazhong University of Science and Technology for technique support in two-photon microscopy imaging. Supported by grants from the US National Institute of Neurological Disorders and Stroke, National Institutes of Health NS075136 and NS091144 (J.B.D.), the Klingenstein Foundation (J.B.D.), the National Natural Science Foundation of China no. 91132726, 91232306 and 81327802 (T.X.), Science Fund for Creative Research Groups of the National Natural Science Foundation of China no. 61421064, the Fundamental Research Funds for the Central Universities, HUST:2014XJGH004 (T.X.), the Director Fund of the Wuhan National Laboratory for Optoelectronics, and a Stanford Neuroscience Institute Postdoctoral Scholarship (R.R.L.).

Author information

Author notes

  1. Lili Guo, Huan Xiong, Jae-Ick Kim and Yu-Wei Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics–Huazhong University of Science and Technology, Wuhan, China

    Lili Guo, Huan Xiong, Yuting Cui, Yu Shu & Tonghui Xu

  2. Department of Biomedical Engineering, Ministry of Education (MoE) Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, China

    Lili Guo, Huan Xiong, Yuting Cui, Yu Shu & Tonghui Xu

  3. Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, USA

    Jae-Ick Kim, Yu-Wei Wu, Rupa R Lalchandani & Jun B Ding

  4. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA

    Jae-Ick Kim, Yu-Wei Wu, Rupa R Lalchandani & Jun B Ding

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Contributions

T.X. and J.B.D. designed the experiments, performed pilot experiments and supervised the project. L.G., H.X.,Y.C., Y.S. and T.X. performed in vivo imaging experiments, J.-I.K. and J.B.D. performed the electrophysiology experiments, Y.-W.W. performed two-photon uncaging experiments. T.X., R.R.L. and J.B.D. wrote the manuscripts with contributions from all authors.

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Correspondence to Tonghui Xu or Jun B Ding.

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Integrated supplementary information

Supplementary Figure 1 Confocal images of sections processed for TH immunoreactivity.

Sections taken from control (a-c), 1 day MPTP (d-f), 4 days MPTP (g-i), and 8 days MPTP (j-l) treated mice. Left (a, d, g, j): low magnification. White box indicates the region of interest (ROI). Right: high magnification images of TH+ dopamine neurons inside the ROI. Following MPTP-treatment, there is significant loss of dopamine neurons in VTA (b, e, h, k) and SNc (c, f, i, l). Scale bar = 100 μm for panels j and 50 μm in panels b, c, e, f, h, i, k and l. The loss of dopamine neurons in SNc after 1d MPTP-treatment: 5.2 ± 8.3%, n = 4 mice, P = 0.3429, Mann-Whitney; after 4d MPTP-treatment: 25.2 ± 2.8%, n = 4 mice, P = 0.0286, Mann-Whitney; after 8d MPTP-treatment: 46.7 ± 2.9%, n = 4 mice, P = 0.0286, Mann-Whitney. The loss of dopamine neurons in VTA after 1d MPTP-treatment: 2.8 ± 3.0%, n = 4 mice, P = 0.8557, Mann-Whitney; after 4d MPTP-treatment: 8.1 ± 1.6%, n = 4 mice, P = 0.0408, Mann-Whitney; after 8d MPTP-treatment: 8.8 ± 1.1%, n = 4 mice, P = 0.0294, Mann-Whitney.

Supplementary Figure 2 No significant loss in number of TH+ neurons in locus coeruleus (LC) after 4 d MPTP treatment.

(a) Mouse atlas illustrating tissue sections. Red box indicates the region of interest (ROI). (b-c) Confocal images of TH+ noradrenergic neurons inside the ROI. Sections were taken from control (b), and 4 days MPTP-treated mice (c). Following MPTP-treatment, there is no significant loss of noradrenergic neurons in LC (n = 269.8 ± 5.6 neurons in control, n = 251 ± 8.4 neurons in MPTP treated group; N = 8-11 consecutive sections from 4 mice in each group; P = 0.1173, Mann-Whitney).

Supplementary Figure 3 Spine dynamics after raclopride injections.

(a) Summary statistics of percentages of spines eliminated (left) and formed (right) over 4 days in the motor cortex of control, and Raclopride-injected mice (Spine elimination – Raclopride: 6.8 ± 0.5%, n = 4 mice; control: 6.5 ± 0.3%, n = 5 mice; P = 0.7302; Spine formation – Raclopride: 9.2 ± 0.8%, n = 4 mice; control: 5.1 ± 0.7%, n = 5 mice, *P = 0.0159, n.s.: non-significant, Mann-Whitney). Box-and-whisker plot indicates the median (middle line), 25th, 75th (box), minimum and maximum (whiskers) percentiles of data (The number in brackets indicates the number of animal used for analysis).

Supplementary Figure 4 TH immunofluorescence in M1 after 6-OHDA injections.

(a) Illustration of 6-OHDA injections into M1 and striatum. Injection needle was inserted lateral or posterior to the imaging window. (b) Representative high magnification images of M1 demonstrating TH immunofluorescence in the contralateral and ipsilateral hemispheres in 6-OHDA injected mice.

Supplementary Figure 5 LTP in barrel cortex is not impaired following dopamine depletion.

(a) Representative experiment illustrating LTP induction. A pairing protocol (360 pulses, 2 Hz, +10 mV postsynaptic depolarization) induced significant LTP in layer V pyramidal neurons in barrel cortex of a control mouse. (b) Representative experiment showing LTP induction in layer V pyramidal neurons in barrel cortex of a reserpine-injected mouse. (c) Summary data showing LTP inductions in control (black) and reserpine (red) conditions. Peak EPSC amplitudes (mean ± SEM) are shown over time (Inset: average EPSCs before (1) and after (2) LTP induction). (d) EPSC amplitude 25-30 min after LTP induction in control and reserpine groups (control: 148.4 ± 14.95%, n = 5 cells from 4 mice, Reserpine: 163.5 ± 39.97%, n = 5 cells from 3 mice). Box-and-whisker plot indicates the median (middle line), 25th, 75th (box), minimum and maximum (whiskers) percentiles of data (The numbers in brackets indicate the number of neurons recorded, n.s.: non-significant, P = 1, compared to control group, Mann-Whitney).

Supplementary Figure 6 Proposed model for spine formation and elimination.

(a) D1 and D2 receptor signaling separately regulate de novo spine formation and spine elimination. Spine stabilization requires LTP. D2 receptor signaling selectively regulates spine formation, while D1 receptor signaling selectively regulates spine stabilization and elimination. LTP is required for stabilization of dendritic spines, and lack of LTP leads to increased spine elimination.

Supplementary Figure 7 Two-photon glutamate uncaging.

(a) 2-photon image of a cortical pyramidal neuron and uncaging evoked EPSCs. Red closed circles represent uncaging locations. (b) Normalized EPSC amplitudes plotted against distance between uncaging location and spines. (c) Ca2+ transients (ΔG/R) and their quantification (right) collected in line scan (yellow line in a). (d) Normalized Ca2+ transient plotted against distance. Uncaging of glutamate evokes a Ca2+ transient and EPSCs in spines with submicron precision.

Supplementary Figure 8 Spine survival following SCH23390, MPTP and haloperidol treatments.

(a) Percentage of surviving new spines (formed between day 0 and day 4) on day 8 for control, SCH23390, MPTP and Haloperidol-injected mice. Survival rate of newly formed spines in MPTP-injected mice were significantly lower than that of Haloperidol-injected mice (MPTP: 37.7 ± 1.9%, n = 6 mice, Haloperidol: 45.7 ± 2.3%, n = 6 mice). The rates of forming new spines were very low in control and SCH23390-injected mice (~5-6%), in addition, the numbers of survived newly formed spines are also low in control mice (n = 15 out of 1171 spines, 1.28%) and SCH23390-injected mice (n = 9 out of 823 spines, 1.09%), which prevented us to achieve meaningful comparison on survival rate of newly formed spines in these mice. Box-and-whisker plot indicates the median (middle line), 25th, 75th (box), minimum and maximum (whiskers) percentiles of data (*P = 0.0152, Mann-Whitney).

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1 and 2 (PDF 1528 kb)

Supplementary Methods Checklist (PDF 612 kb)

De novo spine formation example 1

Representative example 1 showing that a spine is induced by MNI-glutamate uncaging. The yellow dot marks the uncaging position. (AVI 1279 kb)

De novo spine formation example 2

Representative example 2 showing that a spine is induced by MNI-glutamate uncaging. The yellow dot marks the uncaging position. (AVI 944 kb)

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Guo, L., Xiong, H., Kim, JI. et al. Dynamic rewiring of neural circuits in the motor cortex in mouse models of Parkinson's disease. Nat Neurosci 18, 1299–1309 (2015). https://doi.org/10.1038/nn.4082

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