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High/Correlated activity

Magic. Magic. LTP. LTD. High/Correlated activity. Low/uncorrelated activity. High NMDA-R activation. Moderate NMDA-R activation. High Calcium. Moderate Calcium. LTP. LTD. What changes during the expression of synaptic plasticity? Is expression pre or post-synaptic

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High/Correlated activity

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  1. Magic Magic LTP LTD High/Correlated activity Low/uncorrelated activity High NMDA-R activation Moderate NMDA-R activation High Calcium Moderate Calcium LTP LTD

  2. What changes during the expression of synaptic plasticity? • Is expression pre or post-synaptic • What are the mechanisms leading from induction to expression

  3. What can change during synaptic plasticity? • Presynaptic release probability • The number of postsynaptic receptors. • Properties of postsynaptic receptors

  4. A single mini Induced release is multi-quantal

  5. Statistics of the quantal hypothesis: • N available vesicles • Pr- prob. Of release Binomial statistics:

  6. Binomial statistics: Examples • N available vesicles • Pr- prob. Of release mean: variance: Note – in real data, the variance is larger

  7. Possible evidence for a pre-synaptic mechanism • Change in failure rate (minimal stimulation) Probability of failure: N vesicles, Pr – prob of release

  8. 2. Change in coefficient of variation CV Assume a synapse with N vesicles available for release each with a probability of release Pr and each vesicle released causes a postsynaptic response with magnitude μ. The mean response is: The variance is: The CV2 (variance/mean2 ) is:

  9. Plot on matlab CV2 vs Pr and vs. N:

  10. 3. Change in paired pulse ratio (PPR) Short term synaptic dynamics: depression facilitation

  11. Synaptic depression: • Nr- vesicles available for release. • Pr- probability of release. • Upon a release event NrPr of the vesicles are moved to another pool, not immediately available (Nu). • Used vesicles are recycled back to available pool, with a time constant τu

  12. Nr Nu 1/τu Therefore: And for many AP’s:

  13. Show examples of short term depression. How might facilitation work?

  14. Nr Nu 1/τu Postsynaptic spine Are there other possible reasons for change in PPR?

  15. 4. Open channel blocker MK-801

  16. Evidence for postsynaptic change: • No change in failures • No change in CV • No change in PPR • No change in MK-801 • Change in the magnitude of successful transmission • No change in NMDA-R component

  17. The story of silent synapses before after

  18. The story of silent synapses • Concepts • Minimal stimulation • Effect of depolarization on NMDA-R

  19. Model of synaptic plasticity

  20. Mechanisms for the induction of synaptic plasticity • Phosphorylation of receptors • Phosphatases, Kinases and Calcium • How do we model the Phosphorylation cycle • Receptor trafficking • Receptor trafficking and Phosphorylation

  21. Phosphorylation state of Gultamate receptors is correlated with LTP and LTD GluR1-4, functional units are heteromers, probably composed of 4 subunits, probably composes of different subtypes. Many are composed of GluR1 and GluR2 R2 P R1 R1 P R2

  22. Protein Phosphorylation Non-phosphorylated Phosphorylated Phosphorylation at s831 and s845 both increase conductance but in different ways

  23. LTD- dephosphorylation at ser 845 Lee et al. 2000

  24. LTP- phosphorylation at ser 831

  25. Trafficking of Glutamate receptors constitutive and activity dependent. Activity dependent insertion and removal and its dependence on Phosphorylation

  26. Malinow, Malenka 2002

  27. There are two trafficking pathways: 1- Short, in which there is constant plasticity independent trafficking. But dephosphorylation at ser 880 on GluR2 might still trigger LTD. 2- Long, in which phosphorylation triggers LTP. Note – Phosphorylation also increases conductance directly

  28. Magic Magic Dephosphorylation Phosphorylation decreased conductance decreased AMPAR number Increased conductance Increased AMPAR number LTP LTD High/Correlated activity Low/uncorrelated activity High Calcium Moderate Calcium

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