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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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Cumulative probability distribution for SF-AMPA and Max-AMPA recorded at retinogeniculate synapses according to H2-Db GenotypeMax-AMPA (a) and SF-AMPA (b) showed similar cumulative probability histograms between WT (black line) and KbDb−/−;NSEDb+ (broken gray line) and KbDb−/− (broken black line) and KbDb−/−;NSEDb− (gray line). Number of experiments are the same as in the main text, except for Max-AMPA: for KbDb−/−;NSEDb−: n=18 cells/N=5 animals; for KbDb−/−;NSEDb+: n=16/N=7 (p>0.05, Mann-Whitney). Fiber Fraction calculated from Max-AMPA and SF-AMPA measurements is similar between WT and KbDb−/−;NSEDb+ (Figure 2D).
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Figure 9: Cumulative probability distribution for SF-AMPA and Max-AMPA recorded at retinogeniculate synapses according to H2-Db GenotypeMax-AMPA (a) and SF-AMPA (b) showed similar cumulative probability histograms between WT (black line) and KbDb−/−;NSEDb+ (broken gray line) and KbDb−/− (broken black line) and KbDb−/−;NSEDb− (gray line). Number of experiments are the same as in the main text, except for Max-AMPA: for KbDb−/−;NSEDb−: n=18 cells/N=5 animals; for KbDb−/−;NSEDb+: n=16/N=7 (p>0.05, Mann-Whitney). Fiber Fraction calculated from Max-AMPA and SF-AMPA measurements is similar between WT and KbDb−/−;NSEDb+ (Figure 2D).

Mentions: In KbDb−/−;NSEDb+ LGN neurons, only 1–2 EPSC steps could be evoked in response to increasing OT stimulus intensity (Figure 2a), similar to the mature WT innervation pattern (cf Figure 1b) but very different from littermate KbDb−/−;NSEDb− controls (Figure 2b). Minimal stimulation also revealed an increase in SF-AMPA strength (Figure 2c; Extended Data Figures 1c, 4b). Max-AMPA is similar between these genotypes (Extended Data Figure 4a); thus fiber fraction in KbDb−/−;NSEDb+ LGN neurons is 56%, vs 25% in KbDb−/−;NSEDb− neurons (Figure 2d) - also strikingly similar to WT (cf Figure 1e). Thus, expression of H2-Db in neurons rescues RGC synapse elimination in LGN of KbDb−/− close to WT levels.


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)

Cumulative probability distribution for SF-AMPA and Max-AMPA recorded at retinogeniculate synapses according to H2-Db GenotypeMax-AMPA (a) and SF-AMPA (b) showed similar cumulative probability histograms between WT (black line) and KbDb−/−;NSEDb+ (broken gray line) and KbDb−/− (broken black line) and KbDb−/−;NSEDb− (gray line). Number of experiments are the same as in the main text, except for Max-AMPA: for KbDb−/−;NSEDb−: n=18 cells/N=5 animals; for KbDb−/−;NSEDb+: n=16/N=7 (p>0.05, Mann-Whitney). Fiber Fraction calculated from Max-AMPA and SF-AMPA measurements is similar between WT and KbDb−/−;NSEDb+ (Figure 2D).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4016165&req=5

Figure 9: Cumulative probability distribution for SF-AMPA and Max-AMPA recorded at retinogeniculate synapses according to H2-Db GenotypeMax-AMPA (a) and SF-AMPA (b) showed similar cumulative probability histograms between WT (black line) and KbDb−/−;NSEDb+ (broken gray line) and KbDb−/− (broken black line) and KbDb−/−;NSEDb− (gray line). Number of experiments are the same as in the main text, except for Max-AMPA: for KbDb−/−;NSEDb−: n=18 cells/N=5 animals; for KbDb−/−;NSEDb+: n=16/N=7 (p>0.05, Mann-Whitney). Fiber Fraction calculated from Max-AMPA and SF-AMPA measurements is similar between WT and KbDb−/−;NSEDb+ (Figure 2D).
Mentions: In KbDb−/−;NSEDb+ LGN neurons, only 1–2 EPSC steps could be evoked in response to increasing OT stimulus intensity (Figure 2a), similar to the mature WT innervation pattern (cf Figure 1b) but very different from littermate KbDb−/−;NSEDb− controls (Figure 2b). Minimal stimulation also revealed an increase in SF-AMPA strength (Figure 2c; Extended Data Figures 1c, 4b). Max-AMPA is similar between these genotypes (Extended Data Figure 4a); thus fiber fraction in KbDb−/−;NSEDb+ LGN neurons is 56%, vs 25% in KbDb−/−;NSEDb− neurons (Figure 2d) - also strikingly similar to WT (cf Figure 1e). Thus, expression of H2-Db in neurons rescues RGC synapse elimination in LGN of KbDb−/− close to WT levels.

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