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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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Intact release probability at KbDb−/− retinogeniculate synapses before eye-openingPaired pulse stimulation was delivered to the OT at 10Hz, similar to the natural firing frequency of RGCs (Extended Data Figure 2c), and whole cell recordings were made from LGN neurons in slices aged between P8–13. Paired pulse stimulation resulted in synaptic depression, represented as EPSC 2 divided by EPSC 1 (%). In 0 μM CTZ (left panel): WT: 67.0±2.9 (n=11/N=4); KbDb−/−: 64.2±2.8 (n=7/N=2). In 20 μM CTZ, (right panel): WT: 48.6±4.9 (n=8/N=3); KbDb−/−: 46.6±2.5 (n=7/N=2) (p>0.1 for each, t-test). mean±s.e.m. 20 mM BAPTA containing Cs+-internal solution was used for this experiment due to prolonged kinetics of EPSCs in KbDb−/−. The identical paired pulse ratios between WT and KbDb−/− are consistent with the conclusion that presynaptic release probability is intact at P8–13 retinogeniculate synapses in KbDb−/− mice. (See also Extended Data Figure 1e–h for similar conclusion at P20–24, after synapse elimination is largely complete.)
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Figure 11: Intact release probability at KbDb−/− retinogeniculate synapses before eye-openingPaired pulse stimulation was delivered to the OT at 10Hz, similar to the natural firing frequency of RGCs (Extended Data Figure 2c), and whole cell recordings were made from LGN neurons in slices aged between P8–13. Paired pulse stimulation resulted in synaptic depression, represented as EPSC 2 divided by EPSC 1 (%). In 0 μM CTZ (left panel): WT: 67.0±2.9 (n=11/N=4); KbDb−/−: 64.2±2.8 (n=7/N=2). In 20 μM CTZ, (right panel): WT: 48.6±4.9 (n=8/N=3); KbDb−/−: 46.6±2.5 (n=7/N=2) (p>0.1 for each, t-test). mean±s.e.m. 20 mM BAPTA containing Cs+-internal solution was used for this experiment due to prolonged kinetics of EPSCs in KbDb−/−. The identical paired pulse ratios between WT and KbDb−/− are consistent with the conclusion that presynaptic release probability is intact at P8–13 retinogeniculate synapses in KbDb−/− mice. (See also Extended Data Figure 1e–h for similar conclusion at P20–24, after synapse elimination is largely complete.)

Mentions: Synapse elimination is thought to involve cellular processes leading to synaptic weakening such as LTD24,25; conversely LTP-like mechanisms are postulated for synaptic strengthening and stabilization26,27. In addition, spike timing-dependent mechanisms are crucial in Xenopus tectum for visually-driven tuning of receptive fields28. In mammalian LGN, LTP29 or LTD30 can be induced at retinogeniculate synapses using 100 Hz OT stimulation, which is far from the endogenous bursting patterns generated by retinal waves (Figure 1f,g)1–4. However, realistic patterns of OT stimulation mimicking waves, paired with postsynaptic depolarization of LGN neurons have also been used; results revealed a synaptic learning rule that generates LTP when pre- and postsynaptic activity are coincident31,32, but LTD when presynaptic OT activity precedes postsynaptic LGN depolarization within a broad window corresponding to the 60–90 second duty cycle of retinal waves (Figure 3a–c; Extended Data Figure 2b)31. Moreover, using these timing patterns in conjunction with optogenetic stimulation of retina is sufficient either to drive or prevent segregation of RGC axons depending on the pattern33. To determine if synaptic learning rules based on natural activity patterns are altered at KbDb−/− retinogeniculate synapses, perforated patch recordings were made in LGN slices from WT vs KbDb−/− at P8–13, the relevant period when extensive synapse elimination and eye-specific segregation are actually occurring. First, paired pulse stimulation was used to examine release probability: the same amount of synaptic depression was observed in WT and KbDb−/−, implying similar probabilities. (Extended Data Figure 6). Next, synchronous activity patterns were used, in which 10 Hz OT stimulation was paired with LGN depolarization (Figure 3a,b: 0 ms latency), generating 10–20 Hz bursts of action potentials in LGN neurons mimicking retinal waves4,5. In WT, synchronous stimulation induced long-term synaptic potentiation (LTP) (Figure 3d,f; 117±8 % over baseline; p<0.001). In KbDb−/− LGN neurons, the same protocol elicited LTP indistinguishable from WT (Figure 3e,f).


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)

Intact release probability at KbDb−/− retinogeniculate synapses before eye-openingPaired pulse stimulation was delivered to the OT at 10Hz, similar to the natural firing frequency of RGCs (Extended Data Figure 2c), and whole cell recordings were made from LGN neurons in slices aged between P8–13. Paired pulse stimulation resulted in synaptic depression, represented as EPSC 2 divided by EPSC 1 (%). In 0 μM CTZ (left panel): WT: 67.0±2.9 (n=11/N=4); KbDb−/−: 64.2±2.8 (n=7/N=2). In 20 μM CTZ, (right panel): WT: 48.6±4.9 (n=8/N=3); KbDb−/−: 46.6±2.5 (n=7/N=2) (p>0.1 for each, t-test). mean±s.e.m. 20 mM BAPTA containing Cs+-internal solution was used for this experiment due to prolonged kinetics of EPSCs in KbDb−/−. The identical paired pulse ratios between WT and KbDb−/− are consistent with the conclusion that presynaptic release probability is intact at P8–13 retinogeniculate synapses in KbDb−/− mice. (See also Extended Data Figure 1e–h for similar conclusion at P20–24, after synapse elimination is largely complete.)
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Figure 11: Intact release probability at KbDb−/− retinogeniculate synapses before eye-openingPaired pulse stimulation was delivered to the OT at 10Hz, similar to the natural firing frequency of RGCs (Extended Data Figure 2c), and whole cell recordings were made from LGN neurons in slices aged between P8–13. Paired pulse stimulation resulted in synaptic depression, represented as EPSC 2 divided by EPSC 1 (%). In 0 μM CTZ (left panel): WT: 67.0±2.9 (n=11/N=4); KbDb−/−: 64.2±2.8 (n=7/N=2). In 20 μM CTZ, (right panel): WT: 48.6±4.9 (n=8/N=3); KbDb−/−: 46.6±2.5 (n=7/N=2) (p>0.1 for each, t-test). mean±s.e.m. 20 mM BAPTA containing Cs+-internal solution was used for this experiment due to prolonged kinetics of EPSCs in KbDb−/−. The identical paired pulse ratios between WT and KbDb−/− are consistent with the conclusion that presynaptic release probability is intact at P8–13 retinogeniculate synapses in KbDb−/− mice. (See also Extended Data Figure 1e–h for similar conclusion at P20–24, after synapse elimination is largely complete.)
Mentions: Synapse elimination is thought to involve cellular processes leading to synaptic weakening such as LTD24,25; conversely LTP-like mechanisms are postulated for synaptic strengthening and stabilization26,27. In addition, spike timing-dependent mechanisms are crucial in Xenopus tectum for visually-driven tuning of receptive fields28. In mammalian LGN, LTP29 or LTD30 can be induced at retinogeniculate synapses using 100 Hz OT stimulation, which is far from the endogenous bursting patterns generated by retinal waves (Figure 1f,g)1–4. However, realistic patterns of OT stimulation mimicking waves, paired with postsynaptic depolarization of LGN neurons have also been used; results revealed a synaptic learning rule that generates LTP when pre- and postsynaptic activity are coincident31,32, but LTD when presynaptic OT activity precedes postsynaptic LGN depolarization within a broad window corresponding to the 60–90 second duty cycle of retinal waves (Figure 3a–c; Extended Data Figure 2b)31. Moreover, using these timing patterns in conjunction with optogenetic stimulation of retina is sufficient either to drive or prevent segregation of RGC axons depending on the pattern33. To determine if synaptic learning rules based on natural activity patterns are altered at KbDb−/− retinogeniculate synapses, perforated patch recordings were made in LGN slices from WT vs KbDb−/− at P8–13, the relevant period when extensive synapse elimination and eye-specific segregation are actually occurring. First, paired pulse stimulation was used to examine release probability: the same amount of synaptic depression was observed in WT and KbDb−/−, implying similar probabilities. (Extended Data Figure 6). Next, synchronous activity patterns were used, in which 10 Hz OT stimulation was paired with LGN depolarization (Figure 3a,b: 0 ms latency), generating 10–20 Hz bursts of action potentials in LGN neurons mimicking retinal waves4,5. In WT, synchronous stimulation induced long-term synaptic potentiation (LTP) (Figure 3d,f; 117±8 % over baseline; p<0.001). In KbDb−/− LGN neurons, the same protocol elicited LTP indistinguishable from WT (Figure 3e,f).

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