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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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Failure of retinogeniculate synapse elimination despite intact retinal waves in KbDb −/−(a–e): Impaired synapse elimination in KbDb−/− at P20–24. (a) Slice preparation used for whole cell recording from dLGN neurons and stimulation of retinal ganglion cell (RGC) axons in the optic tract (OT). The retinogeniculate projection is visualized by injecting CTb AF488 (green) into the contralateral eye. (b, c) EPSC amplitude vs OT stimulus intensity. Insets: example traces. (d) Cumulative probability histograms of single fiber synaptic strength (SF-AMPA). Inset: mean±s.e.m. for WT (n=12/N=6); KbDb−/− (n=23/N=8), *p<0.05 (e) Fiber fraction (FF) for WT (n=12/N=6); KbDb −/− (n=21/N=8), **p<0.01, t-test for (d,e). (f,g): Intact retinal waves in KbDb−/− at P10–12. (f) Raster plots of single-unit spike trains recorded from 10 representative RGCs during retinal waves. (g) Correlation indices vs inter-electrode distance for all cell pairs for WT (N=5) vs KbDb−/− (N=6). Data correspond to mean values of medians from individual datasets and error bars represent s.e.m. n=cells/N=animals.
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Figure 1: Failure of retinogeniculate synapse elimination despite intact retinal waves in KbDb −/−(a–e): Impaired synapse elimination in KbDb−/− at P20–24. (a) Slice preparation used for whole cell recording from dLGN neurons and stimulation of retinal ganglion cell (RGC) axons in the optic tract (OT). The retinogeniculate projection is visualized by injecting CTb AF488 (green) into the contralateral eye. (b, c) EPSC amplitude vs OT stimulus intensity. Insets: example traces. (d) Cumulative probability histograms of single fiber synaptic strength (SF-AMPA). Inset: mean±s.e.m. for WT (n=12/N=6); KbDb−/− (n=23/N=8), *p<0.05 (e) Fiber fraction (FF) for WT (n=12/N=6); KbDb −/− (n=21/N=8), **p<0.01, t-test for (d,e). (f,g): Intact retinal waves in KbDb−/− at P10–12. (f) Raster plots of single-unit spike trains recorded from 10 representative RGCs during retinal waves. (g) Correlation indices vs inter-electrode distance for all cell pairs for WT (N=5) vs KbDb−/− (N=6). Data correspond to mean values of medians from individual datasets and error bars represent s.e.m. n=cells/N=animals.

Mentions: MHCI genes H2-Db and H2-Kb, members of a polymorphic family of over 50, are expressed in LGN neurons10 and were discovered in an unbiased screen in vivo for genes regulated by retinal waves: blocking this endogenous neural activity not only prevents RGC axonal remodeling7, but also downregulates expression of MHCI mRNA12. Previous studies have suggested that MHCI molecules regulate synapse number in cultured neurons13 and are needed for anatomical segregation of RGC axons into LGN layers in vivo10,14. To examine if H2-Kb and H2-Db are involved in functional synapse elimination, whole cell microelectrode recordings were made from individual neurons in WT or KbDb−/− LGN slices (Figure 1a)15,16. Adult mouse LGN neurons normally receive strong monosynaptic inputs from 1–3 RGC axons, but in development, many weak synaptic inputs are present. The majority are eliminated between P5 and P12 prior to eye opening, while the few remaining inputs strengthen resulting in adult-like synaptic innervation by P24-P3015. By gradually increasing OT stimulation intensity, individual RGC axons with progressively higher firing thresholds can be recruited15, generating a stepwise series of EPSCs recorded in each LGN neuron. For example, at P21 in WT, only two steps are present (Figure 1b), indicating that just 2 RGC axons provide input to this LGN neuron, as expected. In contrast, in KbDb−/− LGN neurons, there are many EPSC steps (Figure 1c), a pattern similar to that in much younger WT mice prior to synapse elimination15,16.


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)

Failure of retinogeniculate synapse elimination despite intact retinal waves in KbDb −/−(a–e): Impaired synapse elimination in KbDb−/− at P20–24. (a) Slice preparation used for whole cell recording from dLGN neurons and stimulation of retinal ganglion cell (RGC) axons in the optic tract (OT). The retinogeniculate projection is visualized by injecting CTb AF488 (green) into the contralateral eye. (b, c) EPSC amplitude vs OT stimulus intensity. Insets: example traces. (d) Cumulative probability histograms of single fiber synaptic strength (SF-AMPA). Inset: mean±s.e.m. for WT (n=12/N=6); KbDb−/− (n=23/N=8), *p<0.05 (e) Fiber fraction (FF) for WT (n=12/N=6); KbDb −/− (n=21/N=8), **p<0.01, t-test for (d,e). (f,g): Intact retinal waves in KbDb−/− at P10–12. (f) Raster plots of single-unit spike trains recorded from 10 representative RGCs during retinal waves. (g) Correlation indices vs inter-electrode distance for all cell pairs for WT (N=5) vs KbDb−/− (N=6). Data correspond to mean values of medians from individual datasets and error bars represent s.e.m. n=cells/N=animals.
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Figure 1: Failure of retinogeniculate synapse elimination despite intact retinal waves in KbDb −/−(a–e): Impaired synapse elimination in KbDb−/− at P20–24. (a) Slice preparation used for whole cell recording from dLGN neurons and stimulation of retinal ganglion cell (RGC) axons in the optic tract (OT). The retinogeniculate projection is visualized by injecting CTb AF488 (green) into the contralateral eye. (b, c) EPSC amplitude vs OT stimulus intensity. Insets: example traces. (d) Cumulative probability histograms of single fiber synaptic strength (SF-AMPA). Inset: mean±s.e.m. for WT (n=12/N=6); KbDb−/− (n=23/N=8), *p<0.05 (e) Fiber fraction (FF) for WT (n=12/N=6); KbDb −/− (n=21/N=8), **p<0.01, t-test for (d,e). (f,g): Intact retinal waves in KbDb−/− at P10–12. (f) Raster plots of single-unit spike trains recorded from 10 representative RGCs during retinal waves. (g) Correlation indices vs inter-electrode distance for all cell pairs for WT (N=5) vs KbDb−/− (N=6). Data correspond to mean values of medians from individual datasets and error bars represent s.e.m. n=cells/N=animals.
Mentions: MHCI genes H2-Db and H2-Kb, members of a polymorphic family of over 50, are expressed in LGN neurons10 and were discovered in an unbiased screen in vivo for genes regulated by retinal waves: blocking this endogenous neural activity not only prevents RGC axonal remodeling7, but also downregulates expression of MHCI mRNA12. Previous studies have suggested that MHCI molecules regulate synapse number in cultured neurons13 and are needed for anatomical segregation of RGC axons into LGN layers in vivo10,14. To examine if H2-Kb and H2-Db are involved in functional synapse elimination, whole cell microelectrode recordings were made from individual neurons in WT or KbDb−/− LGN slices (Figure 1a)15,16. Adult mouse LGN neurons normally receive strong monosynaptic inputs from 1–3 RGC axons, but in development, many weak synaptic inputs are present. The majority are eliminated between P5 and P12 prior to eye opening, while the few remaining inputs strengthen resulting in adult-like synaptic innervation by P24-P3015. By gradually increasing OT stimulation intensity, individual RGC axons with progressively higher firing thresholds can be recruited15, generating a stepwise series of EPSCs recorded in each LGN neuron. For example, at P21 in WT, only two steps are present (Figure 1b), indicating that just 2 RGC axons provide input to this LGN neuron, as expected. In contrast, in KbDb−/− LGN neurons, there are many EPSC steps (Figure 1c), a pattern similar to that in much younger WT mice prior to synapse elimination15,16.

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