Synapse elimination and learning rules co-regulated by MHC class I H2-Db.
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.
Departments of Biology and Neurobiology and Bio-X, James H. Clark Center, 318 Campus Drive, Stanford, California 94305, USA.
Hanmi
H
Lee
Departments of Biology and Neurobiology and Bio-X, James H. Clark Center, 318 Campus Drive, Stanford, California 94305, USA.
Barbara K
BK
Brott
Department of Molecular and Cell Biology & Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA.
Lowry A
LA
Kirkby
Departments of Biology and Neurobiology and Bio-X, James H. Clark Center, 318 Campus Drive, Stanford, California 94305, USA.
Jaimie D
JD
Adelson
Departments of Biology and Neurobiology and Bio-X, James H. Clark Center, 318 Campus Drive, Stanford, California 94305, USA.
Sarah
S
Cheng
Department of Molecular and Cell Biology & Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA.
Marla B
MB
Feller
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.
Akash
A
Datwani
Departments of Biology and Neurobiology and Bio-X, James H. Clark Center, 318 Campus Drive, Stanford, California 94305, USA.
Carla J
CJ
Shatz
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005829:Geniculate Bodies / Q000166:cytology* / Q000502:physiology*; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology; D036881:Long-Term Synaptic Depression; D051379:Mice; D009434:Neural Pathways; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000502:physiology; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium