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

Lee H, Brott BK, Kirkby LA, Adelson JD, Cheng S, Feller MB, Datwani A, Shatz CJ - Nature (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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

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Increased Ca2+-permeable AMPA receptors at retinogeniculate synapses in KbDb−/− LGN(a–d): Prolonged decay kinetics of IAMPA in KbDb−/−. (a) Average IAMPA (5–10 EPSCs) for WT vs KbDb−/− LGN neurons (b) IAMPA Half width (ms), (c) IAMPA decay time (ms) and (d) Peak amplitude (nA) for WT vs KbDb−/− (WT: n=16/N=4; KbDb−/−: n=22/N=5). (e) Increased % inhibition of peak IAMPA by NASPM (100 μM) in KbDb−/− (n=13/N=4) vs WT (n=9/N=3) (**p<0.01; n.s.: not significant; Mann-Whitney for b–c). (f) IAMPA I–V curves (normalized to −40 mV). (g) Rectification Index (RI) for WT (n=14/N=3), KbDb−/− (n=9/N=3), KbDb−/− +20 μM NASPM (n=16/N=4) or KbDb−/− +100 μM NASPM (n=6/N=2) (***p<0.001 for WT vs KbDb−/−; p>0.05 for WT vs KbDb−/− +NASPM (20 or 100 μM), Mann-Whitney). Ages studied: P8–13. Also see Extended Data Figure 7. n=cells/N=animals.
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Figure 4: Increased Ca2+-permeable AMPA receptors at retinogeniculate synapses in KbDb−/− LGN(a–d): Prolonged decay kinetics of IAMPA in KbDb−/−. (a) Average IAMPA (5–10 EPSCs) for WT vs KbDb−/− LGN neurons (b) IAMPA Half width (ms), (c) IAMPA decay time (ms) and (d) Peak amplitude (nA) for WT vs KbDb−/− (WT: n=16/N=4; KbDb−/−: n=22/N=5). (e) Increased % inhibition of peak IAMPA by NASPM (100 μM) in KbDb−/− (n=13/N=4) vs WT (n=9/N=3) (**p<0.01; n.s.: not significant; Mann-Whitney for b–c). (f) IAMPA I–V curves (normalized to −40 mV). (g) Rectification Index (RI) for WT (n=14/N=3), KbDb−/− (n=9/N=3), KbDb−/− +20 μM NASPM (n=16/N=4) or KbDb−/− +100 μM NASPM (n=6/N=2) (***p<0.001 for WT vs KbDb−/−; p>0.05 for WT vs KbDb−/− +NASPM (20 or 100 μM), Mann-Whitney). Ages studied: P8–13. Also see Extended Data Figure 7. n=cells/N=animals.

Mentions: Impaired LTD in KbDb−/− could be due to altered regulation of NMDA receptor mediated synaptic responses, since LTP and LTD are known to be dependent on NMDA receptors at a variety of synapses26. Surprisingly the NMDA/AMPA ratio was not different between genotypes (Extended Data Figure 7a,b). However, the kinetics of IAMPA recorded in KbDb−/− LGN neurons are markedly prolonged compared to WT (Figure 4a–d). The slowed decay in KbDb−/− EPSCs is unlikely due to different peak IAMPA amplitudes (p>0.1; Figure 4d), but could occur if there were greater Ca2+ infux through AMPA receptors.


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

Lee H, Brott BK, Kirkby LA, Adelson JD, Cheng S, Feller MB, Datwani A, Shatz CJ - Nature (2014)

Increased Ca2+-permeable AMPA receptors at retinogeniculate synapses in KbDb−/− LGN(a–d): Prolonged decay kinetics of IAMPA in KbDb−/−. (a) Average IAMPA (5–10 EPSCs) for WT vs KbDb−/− LGN neurons (b) IAMPA Half width (ms), (c) IAMPA decay time (ms) and (d) Peak amplitude (nA) for WT vs KbDb−/− (WT: n=16/N=4; KbDb−/−: n=22/N=5). (e) Increased % inhibition of peak IAMPA by NASPM (100 μM) in KbDb−/− (n=13/N=4) vs WT (n=9/N=3) (**p<0.01; n.s.: not significant; Mann-Whitney for b–c). (f) IAMPA I–V curves (normalized to −40 mV). (g) Rectification Index (RI) for WT (n=14/N=3), KbDb−/− (n=9/N=3), KbDb−/− +20 μM NASPM (n=16/N=4) or KbDb−/− +100 μM NASPM (n=6/N=2) (***p<0.001 for WT vs KbDb−/−; p>0.05 for WT vs KbDb−/− +NASPM (20 or 100 μM), Mann-Whitney). Ages studied: P8–13. Also see Extended Data Figure 7. n=cells/N=animals.
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Figure 4: Increased Ca2+-permeable AMPA receptors at retinogeniculate synapses in KbDb−/− LGN(a–d): Prolonged decay kinetics of IAMPA in KbDb−/−. (a) Average IAMPA (5–10 EPSCs) for WT vs KbDb−/− LGN neurons (b) IAMPA Half width (ms), (c) IAMPA decay time (ms) and (d) Peak amplitude (nA) for WT vs KbDb−/− (WT: n=16/N=4; KbDb−/−: n=22/N=5). (e) Increased % inhibition of peak IAMPA by NASPM (100 μM) in KbDb−/− (n=13/N=4) vs WT (n=9/N=3) (**p<0.01; n.s.: not significant; Mann-Whitney for b–c). (f) IAMPA I–V curves (normalized to −40 mV). (g) Rectification Index (RI) for WT (n=14/N=3), KbDb−/− (n=9/N=3), KbDb−/− +20 μM NASPM (n=16/N=4) or KbDb−/− +100 μM NASPM (n=6/N=2) (***p<0.001 for WT vs KbDb−/−; p>0.05 for WT vs KbDb−/− +NASPM (20 or 100 μM), Mann-Whitney). Ages studied: P8–13. Also see Extended Data Figure 7. n=cells/N=animals.
Mentions: Impaired LTD in KbDb−/− could be due to altered regulation of NMDA receptor mediated synaptic responses, since LTP and LTD are known to be dependent on NMDA receptors at a variety of synapses26. Surprisingly the NMDA/AMPA ratio was not different between genotypes (Extended Data Figure 7a,b). However, the kinetics of IAMPA recorded in KbDb−/− LGN neurons are markedly prolonged compared to WT (Figure 4a–d). The slowed decay in KbDb−/− EPSCs is unlikely due to different peak IAMPA amplitudes (p>0.1; Figure 4d), but could occur if there were greater Ca2+ infux through AMPA receptors.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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

Show MeSH
Related in: MedlinePlus