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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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NASPM-dependent rescue of LTD in KbDb−/− LGN at P8–13. (a) Summary of all 1100 ms latency experiments: EPSC peak amplitude (% change from baseline) vs time (n=7/N=7 for 0 μM NASPM; n=5/N=5 for 20 μM NASPM). Gray bar=induction period (Methods). 1 min data binning. (b) Average of % change (mean±s.e.m.); KbDb−/− 0 μM NASPM: 105±8.2 (N=7); KbDb−/− +20 μM NASPM: 72.5±2.2 (N=5). **p<0.01, t-test, n=cells/N=animals.
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Figure 13: NASPM-dependent rescue of LTD in KbDb−/− LGN at P8–13. (a) Summary of all 1100 ms latency experiments: EPSC peak amplitude (% change from baseline) vs time (n=7/N=7 for 0 μM NASPM; n=5/N=5 for 20 μM NASPM). Gray bar=induction period (Methods). 1 min data binning. (b) Average of % change (mean±s.e.m.); KbDb−/− 0 μM NASPM: 105±8.2 (N=7); KbDb−/− +20 μM NASPM: 72.5±2.2 (N=5). **p<0.01, t-test, n=cells/N=animals.

Mentions: Differences in composition of GluR subunits are known to modulate AMPA receptor Ca2+ permeability, and tetramers containing GluR2 confer Ca2+ impermeability35. Indeed, the ratio of GluR1 to GluR2, the most prevalent subunits35,37,38, is slightly increased in developing thalamus from KbDb−/− mice (30% increase in KbDb−/−, p=0.07; Extended Data Figure 7e). The thalamus is highly heterogeneous, so we also examined cortical neuronal cultures: the ratio of GluR1 to GluR2 is also significantly increased (230% increase in KbDb−/−; p=0.03; Extended Data Figure 7f). Elevated levels of GluR1 subunits suggest that AMPA receptors in KbDb−/− are more likely to be composed of GluR1 homomers, yielding increased Ca2+ permeability. Together, results point to an increase in CP-AMPA receptors in KbDb−/−. Similar increases in CP-AMPA receptors at other synapses are known to shift synaptic learning rules away from LTD and towards LTP39,40. If so, the deficit in LTD observed with the asynchronous pairing protocol (Figure 3c,i) in KbDb−/− LGN should be rescued using NASPM to block CP-AMPA receptors- just what is observed (Extended Data Figure 8).


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)

NASPM-dependent rescue of LTD in KbDb−/− LGN at P8–13. (a) Summary of all 1100 ms latency experiments: EPSC peak amplitude (% change from baseline) vs time (n=7/N=7 for 0 μM NASPM; n=5/N=5 for 20 μM NASPM). Gray bar=induction period (Methods). 1 min data binning. (b) Average of % change (mean±s.e.m.); KbDb−/− 0 μM NASPM: 105±8.2 (N=7); KbDb−/− +20 μM NASPM: 72.5±2.2 (N=5). **p<0.01, t-test, n=cells/N=animals.
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Figure 13: NASPM-dependent rescue of LTD in KbDb−/− LGN at P8–13. (a) Summary of all 1100 ms latency experiments: EPSC peak amplitude (% change from baseline) vs time (n=7/N=7 for 0 μM NASPM; n=5/N=5 for 20 μM NASPM). Gray bar=induction period (Methods). 1 min data binning. (b) Average of % change (mean±s.e.m.); KbDb−/− 0 μM NASPM: 105±8.2 (N=7); KbDb−/− +20 μM NASPM: 72.5±2.2 (N=5). **p<0.01, t-test, n=cells/N=animals.
Mentions: Differences in composition of GluR subunits are known to modulate AMPA receptor Ca2+ permeability, and tetramers containing GluR2 confer Ca2+ impermeability35. Indeed, the ratio of GluR1 to GluR2, the most prevalent subunits35,37,38, is slightly increased in developing thalamus from KbDb−/− mice (30% increase in KbDb−/−, p=0.07; Extended Data Figure 7e). The thalamus is highly heterogeneous, so we also examined cortical neuronal cultures: the ratio of GluR1 to GluR2 is also significantly increased (230% increase in KbDb−/−; p=0.03; Extended Data Figure 7f). Elevated levels of GluR1 subunits suggest that AMPA receptors in KbDb−/− are more likely to be composed of GluR1 homomers, yielding increased Ca2+ permeability. Together, results point to an increase in CP-AMPA receptors in KbDb−/−. Similar increases in CP-AMPA receptors at other synapses are known to shift synaptic learning rules away from LTD and towards LTP39,40. If so, the deficit in LTD observed with the asynchronous pairing protocol (Figure 3c,i) in KbDb−/− LGN should be rescued using NASPM to block CP-AMPA receptors- just what is observed (Extended Data Figure 8).

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