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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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Normal NMDA/AMPA ratio but increased Ca2+ permeable AMPA receptors at retinogeniculate synapses in KbDb −/−(a,b): NMDA/AMPA ratio is unchanged in KbDb−/−. (a) NMDA/AMPA ratio (%): Peak IAMPA measured at −70 mV (+20 μM SR95531) vs peak INMDA at +40 mV (+20 μM SR95531 + 20 μM DNQX): WT: 61±6.8 (n=10/N=4); KbDb−/−: 70.6 ± 12.1 (n=7/N=3) (p>0.1, t-test). mean±s.e.m. (b) Example recordings from individual neurons for WT (left) and KbDb−/− (right). APV (100 μM) was added at the end of each experiment to confirm NMDA-mediated synaptic currents. D600 in pipette. (c) Example showing effect of NASPM (100 μM bath) on IAMPA: note significant blockade of IAMPA in KbDb−/−. Gray line: prior to NASPM; black line: after NASPM (5 traces averaged for single cell) SR95531 in bath for (a–c). (d) Examples for IAMPA normalized to EPSC amplitude at −40 mV. Note reduction in EPSC amplitude at +40 mV in KbDb−/− but not WT. 100 μM APV + 20 μM SR95531 in bath. Spermine (100 μM) and D600 (100 μM) in pipette. Ages: P8–13. Experimenter was aware of genotype due to obvious differences in time course of EPSCs and effects of NASPM. (e) Example Western blot (left) and GluR1/GluR2 ratio (right) of P22 thalamus; WT: 1.0 ± 0.1 (N=12); KbDb−/−: 1.3 ± 0.1 (N=13) (p=0.07). (f) Example Western blot (left) and GluR1/GluR2 ratio (right) of cultured cortical neurons; WT: 1.0 ± 0.1 (N=4); KbDb−/−: 2.3 ± 0.7 (N=4) (*p=0.03). Mann-Whitney for (e, f), n=cells/N=animals.
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Figure 12: Normal NMDA/AMPA ratio but increased Ca2+ permeable AMPA receptors at retinogeniculate synapses in KbDb −/−(a,b): NMDA/AMPA ratio is unchanged in KbDb−/−. (a) NMDA/AMPA ratio (%): Peak IAMPA measured at −70 mV (+20 μM SR95531) vs peak INMDA at +40 mV (+20 μM SR95531 + 20 μM DNQX): WT: 61±6.8 (n=10/N=4); KbDb−/−: 70.6 ± 12.1 (n=7/N=3) (p>0.1, t-test). mean±s.e.m. (b) Example recordings from individual neurons for WT (left) and KbDb−/− (right). APV (100 μM) was added at the end of each experiment to confirm NMDA-mediated synaptic currents. D600 in pipette. (c) Example showing effect of NASPM (100 μM bath) on IAMPA: note significant blockade of IAMPA in KbDb−/−. Gray line: prior to NASPM; black line: after NASPM (5 traces averaged for single cell) SR95531 in bath for (a–c). (d) Examples for IAMPA normalized to EPSC amplitude at −40 mV. Note reduction in EPSC amplitude at +40 mV in KbDb−/− but not WT. 100 μM APV + 20 μM SR95531 in bath. Spermine (100 μM) and D600 (100 μM) in pipette. Ages: P8–13. Experimenter was aware of genotype due to obvious differences in time course of EPSCs and effects of NASPM. (e) Example Western blot (left) and GluR1/GluR2 ratio (right) of P22 thalamus; WT: 1.0 ± 0.1 (N=12); KbDb−/−: 1.3 ± 0.1 (N=13) (p=0.07). (f) Example Western blot (left) and GluR1/GluR2 ratio (right) of cultured cortical neurons; WT: 1.0 ± 0.1 (N=4); KbDb−/−: 2.3 ± 0.7 (N=4) (*p=0.03). Mann-Whitney for (e, f), 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)

Normal NMDA/AMPA ratio but increased Ca2+ permeable AMPA receptors at retinogeniculate synapses in KbDb −/−(a,b): NMDA/AMPA ratio is unchanged in KbDb−/−. (a) NMDA/AMPA ratio (%): Peak IAMPA measured at −70 mV (+20 μM SR95531) vs peak INMDA at +40 mV (+20 μM SR95531 + 20 μM DNQX): WT: 61±6.8 (n=10/N=4); KbDb−/−: 70.6 ± 12.1 (n=7/N=3) (p>0.1, t-test). mean±s.e.m. (b) Example recordings from individual neurons for WT (left) and KbDb−/− (right). APV (100 μM) was added at the end of each experiment to confirm NMDA-mediated synaptic currents. D600 in pipette. (c) Example showing effect of NASPM (100 μM bath) on IAMPA: note significant blockade of IAMPA in KbDb−/−. Gray line: prior to NASPM; black line: after NASPM (5 traces averaged for single cell) SR95531 in bath for (a–c). (d) Examples for IAMPA normalized to EPSC amplitude at −40 mV. Note reduction in EPSC amplitude at +40 mV in KbDb−/− but not WT. 100 μM APV + 20 μM SR95531 in bath. Spermine (100 μM) and D600 (100 μM) in pipette. Ages: P8–13. Experimenter was aware of genotype due to obvious differences in time course of EPSCs and effects of NASPM. (e) Example Western blot (left) and GluR1/GluR2 ratio (right) of P22 thalamus; WT: 1.0 ± 0.1 (N=12); KbDb−/−: 1.3 ± 0.1 (N=13) (p=0.07). (f) Example Western blot (left) and GluR1/GluR2 ratio (right) of cultured cortical neurons; WT: 1.0 ± 0.1 (N=4); KbDb−/−: 2.3 ± 0.7 (N=4) (*p=0.03). Mann-Whitney for (e, f), n=cells/N=animals.
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Figure 12: Normal NMDA/AMPA ratio but increased Ca2+ permeable AMPA receptors at retinogeniculate synapses in KbDb −/−(a,b): NMDA/AMPA ratio is unchanged in KbDb−/−. (a) NMDA/AMPA ratio (%): Peak IAMPA measured at −70 mV (+20 μM SR95531) vs peak INMDA at +40 mV (+20 μM SR95531 + 20 μM DNQX): WT: 61±6.8 (n=10/N=4); KbDb−/−: 70.6 ± 12.1 (n=7/N=3) (p>0.1, t-test). mean±s.e.m. (b) Example recordings from individual neurons for WT (left) and KbDb−/− (right). APV (100 μM) was added at the end of each experiment to confirm NMDA-mediated synaptic currents. D600 in pipette. (c) Example showing effect of NASPM (100 μM bath) on IAMPA: note significant blockade of IAMPA in KbDb−/−. Gray line: prior to NASPM; black line: after NASPM (5 traces averaged for single cell) SR95531 in bath for (a–c). (d) Examples for IAMPA normalized to EPSC amplitude at −40 mV. Note reduction in EPSC amplitude at +40 mV in KbDb−/− but not WT. 100 μM APV + 20 μM SR95531 in bath. Spermine (100 μM) and D600 (100 μM) in pipette. Ages: P8–13. Experimenter was aware of genotype due to obvious differences in time course of EPSCs and effects of NASPM. (e) Example Western blot (left) and GluR1/GluR2 ratio (right) of P22 thalamus; WT: 1.0 ± 0.1 (N=12); KbDb−/−: 1.3 ± 0.1 (N=13) (p=0.07). (f) Example Western blot (left) and GluR1/GluR2 ratio (right) of cultured cortical neurons; WT: 1.0 ± 0.1 (N=4); KbDb−/−: 2.3 ± 0.7 (N=4) (*p=0.03). Mann-Whitney for (e, f), 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