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Semaphorin 3E–Plexin-D1 signaling controls pathway-specific synapse formation in the striatum

Nature Neuroscience volume 15, pages 215–223 (2012)Cite this article

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Abstract

The proper formation of synaptic connectivity in the mammalian brain is critical for complex behavior. In the striatum, balanced excitatory synaptic transmission from multiple sources onto two classes of principal neurons is required for coordinated and voluntary motor control. Here we show that the interaction between the secreted semaphorin 3E (Sema3E) and its receptor Plexin-D1 is a critical determinant of synaptic specificity in cortico-thalamo-striatal circuits in mice. We find that Sema3e (encoding Sema3E) is highly expressed in thalamostriatal projection neurons, whereas in the striatum Plxnd1 (encoding Plexin-D1) is selectively expressed in direct-pathway medium spiny neurons (MSNs). Despite physical intermingling of the MSNs, genetic ablation of Plxnd1 or Sema3e results in functional and anatomical rearrangement of thalamostriatal synapses specifically in direct-pathway MSNs without effects on corticostriatal synapses. Thus, our results demonstrate that Sema3E and Plexin-D1 specify the degree of glutamatergic connectivity between a specific source and target in the complex circuitry of the basal ganglia.

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Figure 1: Complementary expression pattern of Sema3e and Plxnd1 in the cortex-thalamus-basal ganglia circuit.
Figure 2: Plxnd1 is expressed selectively in direct pathway MSNs in the striatum.
Figure 3: Deletion of Plxnd1 markedly increases mEPSC frequency in direct pathway MSNs.
Figure 4: Deletion of Plxnd1 slightly decreases spine density in direct pathway MSNs.
Figure 5: Deletion of Sema3e increases mEPSC frequency and decreases spine density in direct pathway MSNs.
Figure 6: Postnatal deletion of Plxnd1 perturbs spine density and mEPSC frequency in direct but not indirect pathway MSNs.
Figure 7: Loss of Plxnd1 in direct pathway MSNs selectively increases the strength of thalamostriatal glutamatergic inputs.
Figure 8: Loss of Plxnd1 in direct pathway MSNs increases the number of vGluT2 and GluR1 positive puncta on direct pathway MSNs.

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Acknowledgements

The authors thank L. Ding (Harvard NeuroDiscovery Center) for assistance in image analysis, T. Jessell (Columbia University) and Y. Yoshida (Cincinnati Children's Hospital Medical Center) for providing Plexin-D1 conditional mice, C. Henderson (Columbia University) and F. Mann (Université de la Méditerranée) for Sema3E mice, A. Kautzman, B. Stevens and E. Benecchi for assistance with array tomography and J. Hjorth for assistance with Scholl analysis. We thank members of Sabatini and Gu laboratories for discussions. This work was funded by a Lefler postdoctoral fellowship (W.-J.O.), the Whitehall and Klingenstein foundations (C.G.), the Parkinson's Disease Foundation (PDF-FBS-1106, J.B.D.) and the US National Institute of Neurological Disorders and Stroke (K99-NS075136, J.B.D.; NS046579, B.L.S.; NS064583, C.G.).

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  1. Jun B Ding and Won-Jong Oh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA

    Jun B Ding, Won-Jong Oh, Bernardo L Sabatini & Chenghua Gu

  2. Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA

    Jun B Ding & Bernardo L Sabatini

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  1. Jun B Ding
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Contributions

J.B.D. and W.-J.O. performed the experiments and conducted the data analyses. B.L.S. and C.G. supervised the project. J.B.D., W.-J.O., B.L.S. and C.G. designed the experiments and wrote the manuscript.

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Correspondence to Bernardo L Sabatini or Chenghua Gu.

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Ding, J., Oh, WJ., Sabatini, B. et al. Semaphorin 3E–Plexin-D1 signaling controls pathway-specific synapse formation in the striatum. Nat Neurosci 15, 215–223 (2012). https://doi.org/10.1038/nn.3003

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