Article | Published:

Synapse elimination and learning rules co-regulated by MHC class I H2-Db

Nature volume 509, pages 195200 (08 May 2014) | Download Citation

Abstract

The formation of precise connections between retina and lateral geniculate nucleus (LGN) involves the activity-dependent elimination of some synapses, with strengthening and retention of others. Here we show that the major histocompatibility complex (MHC) class I molecule H2-Db is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-Kb and H2-Db (KbDb−/−), despite intact retinal activity and basal synaptic transmission, the developmentally regulated decrease in functional convergence of retinal ganglion cell synaptic inputs to LGN neurons fails and eye-specific layers do not form. Neuronal expression of just H2-Db in KbDb−/− mice rescues both synapse elimination and eye-specific segregation despite a compromised immune system. When patterns of stimulation mimicking endogenous retinal waves are used to probe synaptic learning rules at retinogeniculate synapses, long-term potentiation (LTP) is intact but long-term depression (LTD) is impaired in KbDb−/− mice. This change is due to an increase in Ca2+-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Restoring H2-Db to KbDb−/− neurons renders AMPA receptors Ca2+ impermeable and rescues LTD. These observations reveal an MHC-class-I-mediated link between developmental synapse pruning and balanced synaptic learning rules enabling both LTD and LTP, and demonstrate a direct requirement for H2-Db in functional and structural synapse pruning in CNS neurons.

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Acknowledgements

We thank members of the Shatz laboratory for helpful comments. For technical assistance, we thank N. Sotelo-Kury, C. Chechelski and P. Kemper. For training in retinogeniculate slice methods, we thank C. Chen, P. Kanold and D. Butts. This work was supported by NIH grants R01 MH071666 and EY02858, and the G. Harold and Leila Y. Mathers Charitable Foundation (C.J.S.); NIH grant RO1 EY13528 (M.B.F.); NDSEG and NSF Graduate Research Fellowships (J.D.A.); and an NSF Graduate Research Fellowship (L.A.K.).

Author information

Author notes

    • Akash Datwani

    Present address: Sage Bionetworks, 1100 Fairview Avenue N., Seattle, Washington 98109, USA.

Affiliations

  1. Departments of Biology and Neurobiology and Bio-X, James H. Clark Center, 318 Campus Drive, Stanford, California 94305, USA

    • Hanmi Lee
    • , Barbara K. Brott
    • , Jaimie D. Adelson
    • , Sarah Cheng
    • , Akash Datwani
    •  & Carla J. Shatz
  2. Department of Molecular and Cell Biology & Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA

    • Lowry A. Kirkby
    •  & Marla B. Feller

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Contributions

H.L. and C.J.S. designed all experiments, analysed and reviewed all results and wrote manuscript. Data contributions are as follows: electrophysiology experiment by H.L.; multi-electrode array experiments by L.A.K. and M.B.F. B.K.B. designed H2-Db monoclonal antibody and performed western blots. H.L. designed and performed RT–PCR experiments. A.D. performed RGC neuronal tract tracing experiments and analysis. J.D.A. and S.C. performed Taqman qPCR.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Carla J. Shatz.

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DOI

https://doi.org/10.1038/nature13154

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