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

Hanmi Lee, Barbara K. Brott, Lowry A. Kirkby, Jaimie D. Adelson, Sarah Cheng, Marla B. Feller, Akash Datwani and Carla J. Shatz ()
Additional contact information
Hanmi Lee: James H. Clark Center, 318 Campus Drive
Barbara K. Brott: James H. Clark Center, 318 Campus Drive
Lowry A. Kirkby: University of California
Jaimie D. Adelson: James H. Clark Center, 318 Campus Drive
Sarah Cheng: James H. Clark Center, 318 Campus Drive
Marla B. Feller: University of California
Akash Datwani: James H. Clark Center, 318 Campus Drive
Carla J. Shatz: James H. Clark Center, 318 Campus Drive

Nature, 2014, vol. 509, issue 7499, 195-200

Abstract: 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-Kband 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.

Date: 2014
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DOI: 10.1038/nature13154

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