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THE AUSTRALIAN NATIONAL UNIVERSITY

THE AUSTRALIAN NATIONAL UNIVERSITY. Short-Term Synaptic Plasticity I Christian Stricker ANUMS /JCSMR - ANU Christian.Stricker@anu.edu.au http://stricker.jcsmr.anu.edu.au /STP1.pptx. Aims. The students should know forms of short-term plasticity (STP) ;

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THE AUSTRALIAN NATIONAL UNIVERSITY

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  1. THE AUSTRALIAN NATIONAL UNIVERSITY Short-Term Synaptic Plasticity IChristian StrickerANUMS/JCSMR - ANUChristian.Stricker@anu.edu.auhttp://stricker.jcsmr.anu.edu.au/STP1.pptx

  2. Aims The students should • know forms of short-term plasticity (STP); • recognise how synaptic efficacy is quantified; • understand the time, over which STP occurs; • be familiar with the 3 phases of plasticity; • appreciate that STP is mostly presynaptic; • be aware of what causes facilitation; • have an understanding of Ca2+sources and extrusion mechanisms; and • appreciate the dynamics involved in STP.

  3. Contents • Defining relevant terms • Different forms of plasticity • Phases: induction, expression, maintenance • Quantifying changes in plasticity: pre- and postsynaptic mechanisms… • Possibilities to alter synaptic efficacy • Facilitation: more than residual Ca2+ • Ca2+ homeostasis in nerve terminals • Sequences in STP: induction and their relief

  4. Synaptic Plasticity • Activity-dependent change in synaptic efficacy • Dependent on previous history of synaptic stimulation • Many different histories of synaptic stimulation • One pulse, two pulses (paired-pulse), multiple pulses, etc. • Different frequencies: slow rate (5 Hz), tetanus (100 Hz), etc. • Forms • Efficacy: • Increase in synaptic efficacy: Potentiation • Other notions used: facilitation, augmentation, habituation • Decrease in synaptic efficacy: Depression • Mostly no other wording used • Timing • Short-term (STP): ms - min (<h) • Long-term: h - d - y(?)

  5. Examples of Plasticity • Form of plasticity is specific to type of synapse (pre- and postsynaptic) and induction protocol. • Purely descriptive - does not imply molecular mechanisms. • Time course of plasticity may provide some clues as to mechanisms. • Different stimuli induce different forms of plasticity.

  6. ThreePhases ofSynapticPlasticity • Induction: Where at the synapse is the change in efficacy STARTED? • Mostly via a Ca2+ influx. • Expression: What are the molecular targets that CAUSE these changes at synapse? • Maintenance: What KEEPSchange in efficacy UP? Of little interest in short-term plasticity (STP) but important in LTP (see later).

  7. Quantifying Synaptic Plasticity • EPSC = npQ • Number of release sites: nPresynaptic • Probability: pPresynaptic • Quantal size: QPostsynaptic • How can efficacy be changed? • n, p, and Q(all of them…) • Increase = potentiation • Decrease = depression

  8. How Could Changes Occur? • Quantal size: Q • Insertion/retrieval of receptors • Unmasking of receptors • Alterations in receptor response • Number of release sites: n • Unmasking of “silent” sites • Unlikely very fast • Probability: p • Excitability of membrane • De-/hyperpolarisation via Na+& K+ channels, etc. • Vesicle availability • Reuptake • Repriming • Ca2+ availability • Action potential shape • Ca2+ channels • Ca2+ handling

  9. Short-Term Plasticity (STP) • All forms share ONE feature, namely that, in general, quantal content (n * p) changes, but not quantal size (Q). • There is a high correlation between changes in n and p. • Conclusion: MOSTLY presynaptic.

  10. Different Forms of STP • Facilitation • Induced by SINGLE action potentials (APs) • Lasts typically a few 10s of ms • Augmentation • Induced by a lot of APs (100 at ~10 Hz) • Lasts typically a few s • Post-tetanicpotentiation (PTP) • Induced by a series of APs (>50 Hz) for several s • Lasts typically a few 10s ofs • Forms can coexist - experimentally often difficult to separate.

  11. Facilitation • Subsequent stimuli result in larger EPSPs. • Often quantified as (here ~ 2x). • Increase for 3rd is bigger than for 2nd. Rozov et al. (2001), J Physiol 531: 807-826.

  12. Calcium and Facilitation • P→B synapse shows strong facilitation. • EGTA as a Ca2+chelator abolishes facilitation: • Facilitation caused by Ca2+ • Ca2+ sensor has lower affinity than that for release: • Ca2+ binds to something other than synaptotagmin to cause facilitation. • Residual Ca2+ hypothesis: • Ca2+ sources • Ca2+ extrusion mechanisms Rozov et al. (2001), J Physiol 531: 807-826.

  13. Ca2+ Sourcing in Terminals • Ca2+channels • VDCC: N, P, Q, R, T, L • TRPC (?) • CRAC (Orai/ STIM1 ?) • Ligand gated channels (ionotropicautoreceptors) • NMDA receptors • AMPA receptors (GluR2-def.) • ACh receptors • Ca2+stores / organelles • SER • IP3 receptors • Ryanodine receptors • Mitochondria • Transporter (Vm!) • NCX: 3 Na+ / 1 Ca2+

  14. Ca2+ Sequestration in Terminals • into extracellular space • Ca2+-ATPase (base load) • Na+/Ca2+ exchanger • into intracellular volume • Organelles: • SERCA pump (SER) • Ψ-uniporter (mitochondria) • Buffers (temporary; cal-pain, calmodulin, etc): • Fixed buffers (fixed proteins - cytoskeleton, membrane bound) • Mobile buffers (soluble proteins, acids, etc.)

  15. Mechanisms of Facilitation • Central is a low p • unlikely release on first AP • depletion not important • Repeated stimulation causes Na+ and Ca2+ load. • Na+/Ca2+-exchanger increases Ca2+→ [Ca2+]res↑: • does not explain total amount of facilitation. • Additional vesicle priming, etc. required. Modified from Zucker (1989), Annu Rev Neurosci 12: 13-31.

  16. Nonlinear Ca2+-Dependence • Ca2+-cooperativity: ≥ 4 Ca2+ bind to release machinery: 4 Ca2+ + X ⇌ XCa2+4 • Numeric example: • Facilitation: 2-fold (100%) • Ca2+ increase: ~5 µM • Ca2+ for release: ~380 µM • Residual Ca2+ cannot account for total facilitation. Dodge & Rahamimoff (1967), J Physiol 193: 419-432.

  17. Ca2+ and Vesicle Mobilisation • One idea - not the only one… • Not all vesicles are free to move: • Some are fixed to actin via synapsin1. • Ca2+-dependent mobilisationof “fixed” vesicles. • Increased vesicle availability. ∴ Idea yet to be tested (difficult…). Walmsley et al. (1998), TINS 21: 81-88.

  18. Mechanisms Causing Facilitation • All phases in presynaptic nerve terminal. • Induction: • [Na+] ↑ → [Ca2+]res↑ • Expression • Non-linear Ca2+ dependence (small) • Ca2+-dependent vesicle mobilisation • Maintenance • Determined by Ca2+ extrusion.

  19. Sequences in STP • Low p hippocampal synapses: small release → facilitation. • Tetanus >50Hz for 12s • Facilitation: fast, initial • Augmentation: slower • Depression: slowest • tbuild-up ≠ trecovery • Contribution of each form relieved during recovery. • Hierarchy of different plasticities: Facilitation →augmentation →depression and vice versa.

  20. Take-Home Messages • Short-term plasticity takes from 10 ms - few min. • Different forms can coexist at a synapse. • Facilitation is associated with low p. • Multiple mechanisms exist to homeostati-cally regulate Ca2+ in nerve terminals. • Mechanisms for facilitation not only include [Ca2+]res but also vesicle priming.

  21. References • Textbooks • Byrne & Roberts “From Molecules to Networks”(2004), pp. 235ff • Kandel et al. (4th ed.), 1247-1254 • Reviews • Zucker RS, Regehr WG (2002) Short-Term Synaptic Plasticity. Ann. Rev. Physiol. 64: 355-405. • Fortune ES, Rose GJ (2001) Short-Term Synaptic Plasticity as a Temporal Filter. Trends Neurosci. 24: 381-385.

  22. That’s it folks…

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