1. CS 2016 Long-Term Synaptic Plasticity III Christian Stricker ANUMS/JCSMR - ANU Christian.Stricker@anu.edu.au http://stricker.jcsmr.anu.edu.au/LTSP2.pptx Christian.Stricker@anu.edu.au http://stricker.jcsmr.anu.edu.au/LTSP2.pptx THE AUSTRALIAN NATIONAL UNIVERSITY

2. CS 2016

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4. CS 2016 Dendritic Shaping of PSPs Boosting of EPSPs Contribution of a NET inward current: EPSP time course↑ –Activation of an inward current. Sodium Calcium (NMDA current or similar) –Inactivation/deactivation of an outward current. Potassium (I A, I K ) Mixed conductance (I h ) ∴ Improved charge transfer from dendrite → soma (LTP). Attenuation of EPSPs Contribution of a NET outward current: EPSP time course↓ –Activation of an outward current Potassium (I A, I K ) Mixed conductance (I h ) (Inhibition: GABA, glycine) –Inactivation/deactivation of an inward current. Sodium Calcium ∴ Reduced charge transfer from dendrite → soma (LTD). Urban et al., J Neurophysiol 98 (1998), 1558 - 1561Clements et al., J Physiol 377 (1986), 267-282

5. CS 2016 How I A Influences EPSPs Presence of I A makes dendrites active. Density of A-channels↑ along dendrite (like I h ). Determines dendritic excitability with EPSPs attenuated (charge ↓). –Predominantly affects EPSP decay phase. –Modulated by STP and LTP (I A ↓). For I A to be fully activated, ∆V of >10 mV (summed EPSPs). After LTP induction –I A for same voltage step ↓, due to inactivation↓ (left shift). –Directly increases excitability. –Causes a larger back-propagating AP. Other conductances involved as well. Magee et al., Ann Rev Physiol 60 (1998):327 Magee & Johnston, CON 15 (2005):334–342

6. CS 2016 Change in Dendritic Excitability Local modulation of active dendritic conductances: improved charge transfer dendrite → soma. –A current ↓. –H current ↓. –and others … Improved AP back-propagation. –Pairing between EPSP-AP in dendritic areas that were spared before. Increase in local plasticity leading to larger local charge accumulation. Improved charge transfer to soma as local I A ↓. –Branch segment plasticity Local depolarisation ↑ causes local NMDA-R dependent spikes. Highly non-linear interaction between voltage- dependent channels, synaptic plasticity, dendritic structure and action potential initiation. Memories may be stored in branch-specific patterns. Likely a different form of information stored than via synapses alone. Sjöström et al., Physiol Rev 88 (2008):769-840

7. CS 2016 Aims At the end of this lecture, the student should be able to know the following properties of LTD: –Induction: protocols, receptors and requirements; –Expression: pre- and postsynaptic factors; and –Maintenance: targets, translation, changes in morphology; be cognisant of concepts involved for switching between the different long-term plasticities; and be able to describe the idea behind metaplasticity.

8. CS 2016 Contents LTD (in contrast to LTP) –Induction: NMDA-R, Ca 2+ and stimulus conditions. –Expression: pre- and postsynaptic targets. –Maintenance: Translation, endocytosis, morphology. “Plasticity of plasticity” –States of synapses and how these can be altered. –Metaplasticity as a result of priming.

9. CS 2016 Long-Term Depression The Little Sister of LTP “A Very Mixed Bucket”

10. CS 2016 Lujan et al., Eur J Neurosci 8 (1996):1488-1500 Otani & Connor, Eur J Pharmacol 318 (1996):R5-6 Induction of LTD Typically low frequency stim. or pairing with AP preceding EPSP. Induction: again postsynaptic Ca 2+. –Postsynaptic Ca 2+ ↑ alone causes LTD Heterosynaptic (non-Hebbian) –[Ca 2+ ] smaller than LTP (0.2 – 0.5 µM). –[Ca 2+ ] rises initially, but then decays. Integral of dendritic Ca 2+ important. “Integrating” phosphatase (?) –In some forms NMDA-R involved. –In others, mGluRs (group I; via PLC or PLA) or N-type VDCC involved. Induction blocked when mGluRs blocked Perisynaptic location (mGluR5) Coincidence of pre- & postsynaptic activity (?). Access to store release in spines (spine app.) VDCC as Ca 2+ source. “De-potentiate” LTP’ed synapses. Many forms may not be “Hebbian”. –Lack specificity, associ- & cooperativity. –Heterosynaptic LTD (when it “spreads”). Tanaka et al., Neuron 54 (2007):787-800 Cormier et al., J Neurophysiol 85 (2001):399-406 Bolshakov & Siegelbaum, Science 264 (1994):1148-1152

11. CS 2016 Expression of LTD: Postsynaptic Expression: over minutes on the postsynaptic side –Ca 2+ activates phosphatase II (calcineurin) → de-phosphorylation of AMPA receptors → AMPA receptor internalisation ↑ → EPSP↓. Synaptic receptors are continually “turned over”; rate is about 40 min for AMPA receptors (very dynamic system). Internalisation dependent on dynamin (like vesicle re-uptake presynaptically): Quantal size↓ –Also NMDA currents ↓ (different to LTP; mechanism unclear (presynaptic?)). –De-phosphorylation of other channels → excitability ↓. Lüscher & Frerking, TINS 24 (2001):665-670

12. CS 2016 Expression of LTD - Presynaptic Presynaptic involvement: –Failure rate ↑. –FM1-43 de-staining rate↓ → p↓. Requires retrograde messenger: NO, arachidonic acid, endocannabinoids (?). –Presynaptic targets are not well understood. Zakharenko et al., Neuron 35 (2002):1099-1110

13. CS 2016 Colledge et al., Neuron 40 (2003):595-607 Maintenance of LTD Much less is known… Maintenance dependent on –translation (anisomycin), Translation of local mRNA Identity of mRNA not known (yet). –but not transcription ( actinomycin ). Different to LTP. Morphological changes –Presynaptic: boutons smaller –Postsynaptic: spines disappear –PSD-95 becomes ubiquitinated degraded via proteasome, causing internalisation of AMPA-R; and reducing size of PSD. Becker et al., Neuron 60 (2008):590-597 Manahan-Vaughan et al., J Neurosci 20 (2002):8572-876

14. CS 2016 Switching between LTP and LTD Metaplasticity The “Plasticity of Synaptic Plasticity”

15. CS 2016 Switching between LTP & LTD Smooth function between type of plasticity and stimulus frequency –at low frequencies: LTD; and –at high frequencies: LTP. –Relationship can be shifted ← or →, ↑ and ↓, depending on conditioning. Experimentally verified (threshold). Non-continuous function between type of plasticity and spike timing: –EPSP – followed by AP: LTP. –AP – followed by EPSP: LTD. –Narrow coincidence required (10’s ms) Synapses can be in different states with defined transition mechanisms. –Central role of NMDA-R to initiate signaling depending on Ca 2+ influx. –“Plasticity” of long-term plasticity. –Neglects dendritic excitability change. Montgomery & Madison, Neuron 33 (2002):765-777 Dudek & Bear, PNAS 89 (1992):4363-4367 Bi & Poo, Ann Rev Neurosci 24 (2001):139-166

16. CS 2016 Metaplasticity Change in the ability to induce subsequent synaptic plasticity (LTP or LTD). Priming has serious impact on subsequent synaptic plasticity. –(Temporary) alteration in NMDA-R function (activity-dependent). –Intracellular Ca 2+ handling / homeostasis. Provides additional complexity to synaptic plasticity (saturation, biochemical signaling). Abraham & Bear, TINS 19 (1996):126-130

17. CS 2016 Take-Home Messages LTD consists of many different forms. –Induction results from smaller Ca 2+ ↑ (different sources). –Expression likely converse to that in LTP. –Maintenance relies on translation & breakdown of PSD. Synapses can be switched into different “states” and either LTP or LTD can result. Priming may give rise to metaplasticity.

18. CS 2016 That’s it folks…