Limits...
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.

Show MeSH

Related in: MedlinePlus

H2-Db expression in neurons rescues synapse elimination and eye-specific segregation in KbDb−/− LGN(a–d): Rescue of synapse elimination at P20–24. (a,b) EPSC amplitudes vs OT stimulus intensity. Insets: example traces. (c) Cumulative probability histogram of SF-AMPA. Inset: mean ± s.e.m. for control: Db− (KbDb−/−;NSEDb−, n=19/N=5). Rescue: Db+ (KbDb−/−;NSEDb+, n=17/N=7), **p<0.01. (d) Fiber Fraction is also rescued in KbDb−/−;NSEDb+ (n=16/N=7) compared to KbDb−/−;NSEDb− (n=18/N=5), *p<0.05, Mann-Whitney for (c–d). Horizontal gray bars delineate Figure 1e data (mean±s.e.m.). (e,f): Rescue of eye-specific segregation in KbDb−/−;NSEDb+ at P34. (e) Top: Coronal sections of dLGN showing pattern of retinogeniculate projections from the ipsi (green) and contralateral (red) eyes. Bottom: Region of ipsi-conta pixel (white) overlap between the two channels at 60% intensity threshold (T60%). (f) % dLGN area occupied by ipsi-contra overlap. mean±s.e.m. for KbDb−/−;NSEDb− (N=3) and KbDb−/−;NSEDb+ (N=4) (T60 %) (*p<0.05, two way ANOVA) (See Extended Data Figure 5). Horizontal gray bar indicates WT value at T60 % (from Datwani et al., 2009)14. n=cells/N=animals.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4016165&req=5

Figure 2: H2-Db expression in neurons rescues synapse elimination and eye-specific segregation in KbDb−/− LGN(a–d): Rescue of synapse elimination at P20–24. (a,b) EPSC amplitudes vs OT stimulus intensity. Insets: example traces. (c) Cumulative probability histogram of SF-AMPA. Inset: mean ± s.e.m. for control: Db− (KbDb−/−;NSEDb−, n=19/N=5). Rescue: Db+ (KbDb−/−;NSEDb+, n=17/N=7), **p<0.01. (d) Fiber Fraction is also rescued in KbDb−/−;NSEDb+ (n=16/N=7) compared to KbDb−/−;NSEDb− (n=18/N=5), *p<0.05, Mann-Whitney for (c–d). Horizontal gray bars delineate Figure 1e data (mean±s.e.m.). (e,f): Rescue of eye-specific segregation in KbDb−/−;NSEDb+ at P34. (e) Top: Coronal sections of dLGN showing pattern of retinogeniculate projections from the ipsi (green) and contralateral (red) eyes. Bottom: Region of ipsi-conta pixel (white) overlap between the two channels at 60% intensity threshold (T60%). (f) % dLGN area occupied by ipsi-contra overlap. mean±s.e.m. for KbDb−/−;NSEDb− (N=3) and KbDb−/−;NSEDb+ (N=4) (T60 %) (*p<0.05, two way ANOVA) (See Extended Data Figure 5). Horizontal gray bar indicates WT value at T60 % (from Datwani et al., 2009)14. n=cells/N=animals.

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)

H2-Db expression in neurons rescues synapse elimination and eye-specific segregation in KbDb−/− LGN(a–d): Rescue of synapse elimination at P20–24. (a,b) EPSC amplitudes vs OT stimulus intensity. Insets: example traces. (c) Cumulative probability histogram of SF-AMPA. Inset: mean ± s.e.m. for control: Db− (KbDb−/−;NSEDb−, n=19/N=5). Rescue: Db+ (KbDb−/−;NSEDb+, n=17/N=7), **p<0.01. (d) Fiber Fraction is also rescued in KbDb−/−;NSEDb+ (n=16/N=7) compared to KbDb−/−;NSEDb− (n=18/N=5), *p<0.05, Mann-Whitney for (c–d). Horizontal gray bars delineate Figure 1e data (mean±s.e.m.). (e,f): Rescue of eye-specific segregation in KbDb−/−;NSEDb+ at P34. (e) Top: Coronal sections of dLGN showing pattern of retinogeniculate projections from the ipsi (green) and contralateral (red) eyes. Bottom: Region of ipsi-conta pixel (white) overlap between the two channels at 60% intensity threshold (T60%). (f) % dLGN area occupied by ipsi-contra overlap. mean±s.e.m. for KbDb−/−;NSEDb− (N=3) and KbDb−/−;NSEDb+ (N=4) (T60 %) (*p<0.05, two way ANOVA) (See Extended Data Figure 5). Horizontal gray bar indicates WT value at T60 % (from Datwani et al., 2009)14. n=cells/N=animals.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: H2-Db expression in neurons rescues synapse elimination and eye-specific segregation in KbDb−/− LGN(a–d): Rescue of synapse elimination at P20–24. (a,b) EPSC amplitudes vs OT stimulus intensity. Insets: example traces. (c) Cumulative probability histogram of SF-AMPA. Inset: mean ± s.e.m. for control: Db− (KbDb−/−;NSEDb−, n=19/N=5). Rescue: Db+ (KbDb−/−;NSEDb+, n=17/N=7), **p<0.01. (d) Fiber Fraction is also rescued in KbDb−/−;NSEDb+ (n=16/N=7) compared to KbDb−/−;NSEDb− (n=18/N=5), *p<0.05, Mann-Whitney for (c–d). Horizontal gray bars delineate Figure 1e data (mean±s.e.m.). (e,f): Rescue of eye-specific segregation in KbDb−/−;NSEDb+ at P34. (e) Top: Coronal sections of dLGN showing pattern of retinogeniculate projections from the ipsi (green) and contralateral (red) eyes. Bottom: Region of ipsi-conta pixel (white) overlap between the two channels at 60% intensity threshold (T60%). (f) % dLGN area occupied by ipsi-contra overlap. mean±s.e.m. for KbDb−/−;NSEDb− (N=3) and KbDb−/−;NSEDb+ (N=4) (T60 %) (*p<0.05, two way ANOVA) (See Extended Data Figure 5). Horizontal gray bar indicates WT value at T60 % (from Datwani et al., 2009)14. n=cells/N=animals.
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