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Nature. 2014 May 8;509(7499):195-200. doi: 10.1038/nature13154. Epub 2014 Mar 30.

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

Author information

1
Departments of Biology and Neurobiology and Bio-X, James H. Clark Center, 318 Campus Drive, Stanford, California 94305, USA.
2
Department of Molecular and Cell Biology & Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA.
3
1] Departments of Biology and Neurobiology and Bio-X, James H. Clark Center, 318 Campus Drive, Stanford, California 94305, USA [2] Sage Bionetworks, 1100 Fairview Avenue N., Seattle, Washington 98109, USA.

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-D(b) is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-K(b) and H2-D(b) (K(b)D(b)(-/-)), 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-D(b) in K(b)D(b)(-/-) 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 K(b)D(b)(-/-) mice. This change is due to an increase in Ca(2+)-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Restoring H2-D(b) to K(b)D(b)(-/-) neurons renders AMPA receptors Ca(2+) 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-D(b) in functional and structural synapse pruning in CNS neurons.

Comment in

PMID:
24695230
PMCID:
PMC4016165
DOI:
10.1038/nature13154
[Indexed for MEDLINE]
Free PMC Article

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