1. CS 2016 Short-Term Synaptic Plasticity II Depression Christian Stricker ANUMS/JCSMR - ANU Christian.Stricker@anu.edu.au http://stricker.jcsmr.anu.edu.au/STP2.pptx Christian.Stricker@anu.edu.au http://stricker.jcsmr.anu.edu.au/STP2.pptx THE AUSTRALIAN NATIONAL UNIVERSITY

2. CS 2016

3. Aims At the end of this lecture, the student should be able to explain why short-term depression (STD) is associated with a high release probability (p); recognise mechanism(s) causing STD; name factors why vesicle recovery is a slow process (~1 s); give details why there are at least 3 different pools of vesicles in the nerve terminal; clarify that the target may determine STP; and identify how STP forms complex temporal filters.

4. CS 2016 Contents Short-term depression (STD) –Depletion –Autoreceptors –Recovery from depression –Evidence for different pools of vesicles For advanced students –Release-independent depression –Frequency-dependent recovery Properties of short-term plasticity Functional role of short-term plasticity

5. CS 2016 Short-Term Plasticity: Depression High p neocortical synapse: easy release… Depression reaches a steady-state after 300 ms. –In steady-state, recovery rate = rate of depression Recovery from depression takes longer than 500 ms (~1 s). STD typically seen at high p synapses.

6. CS 2016 Experimental Set-up

7. CS 2016 Vesicle Depletion and STD p ~ vesicle pool. Depletion causes drop in p. –Recovery longer than stimulus interval (100 ms). –Loss of vesicles faster than replenishment: Replenishment ~.5 - 1 ms (later). Why so slow? –Priming of vesicles (ready). –Filling of vesicles (vGluT). –Glutamate production –Alignment with »exocytotic machinery. »Ca 2+ channels. »presynaptic grid.

8. CS 2016 Experimental Evidence If depletion causes depression, E 1 vs. E 2 must be anti-correlated: –Small E 2 follows large E 1. –Large(r) E 2 follows small E 1. Because transmitter release is stochastic, trial to trial variability: –Dashed line theoretical prediction. –Curve fit to sample (black). In this example, depletion accounts for all depression.

9. CS 2016 Other Mechanisms for STD Autoreceptors: receptors on terminal sense [transmitter] (feedback): –Glutamatergic: Ionotropic: NMDA, AMPA, KA. Metabotropic: Group I – III. –Adenosinergic: Metabotropic: A 1 – A 3 receptors. –Purinergic: Ionotropic: P2X 1-7 Metabotropic: P2Y 1-15 Consequence: VDCC modulation → Ca 2+ influx↓ → release↓: –Activation/inactivation kinetics. –Conductance change. No depression without release ( release-dependent depression ).

10. CS 2016 Phases during Build-Up of STD 100 APs at different frequencies. Plot all EPSCs as a function of stimulus number: –Two phases (at least…): Fast depression early: these vesicles lost immediately (ready to release…). Slow depression later: these vesicles lost at slower rate. –Recovered vesicles (?) –Newly primed vesicles (?) Hierarchy of vesicles, also called different “pools”. Saviane & Silver (2006), Nature 439: 983-987

11. CS 2016 Vesicle Pools Estimates for hippocampal synapse (bouton type; ~ 200 vesicles). At least 3 pools of vesicles involved in release: –Ready-releasable pool (10; RRP): small - fastest release. –Recycling pool (20; RCP): size depends on stimulus frequency; slower. –Reserve pool (170; RP): largest pool with slowest exchange rate. Rizzoli & Betz (2005), Nat Rev Neurosci 6: 57-69

12. CS 2016 Recovery from STD Rate of recovery is same for different stimulus frequencies. Time constant ( τ) ~ 1 s. One rate limiting step (?).

13. CS 2016 Beyond Simple Depletion For Advanced Students

14. CS 2016 STD without Depletion Depletion without anti-correlation –E 2 is “independent” of E 1. –No statistically significant anti-correlation. STD without (much) release: –Release-independent depression (RID) Mechanism(s): –Associated with AP: Within terminal: –Activation/inactivation of conductances at synapse: Na +, K +, Ca 2+. –SNARE “inhibition”. Before terminal: AP failure to invade terminal.

15. CS 2016 Fuhrmann et al. (2004), J Physiol 557: 415-438. Variable Recovery from STD Frequency-dependent recovery (FDR): –At higher stimulus frequencies, recovery rate speeds up. –τ ↓ at ≥ 10 Hz. –τ 50 Hz ~ halved (~0.4 s). Observed at many different synapses. Ca 2+ -dependent process. RID and FDR are correlated. Mechanism: –Relief from STD (?).

16. CS 2016 Mechanism of RID & FDR Most likely mechanism –Gβγ from GPCRs activation (neuromo- dulators ?) binds to SNARE complex (SNAP-25) to inhibit release: RID. –Gβγ binding to SNAP-25 is in compe- tition with Ca 2+ -synaptotagmin-1, which rises during a burst of APs causing relief from RID: FDR. Experimental evidence to date –Serotonin: spinal cord (G i/o ) Alford & Hamm, 2001ff –(Noradrenaline (α 1 ), 5-HT 2 R via G q ) Yoon et al. (2007), Mol Pharmacol 72: 1210-1219.

17. CS 2016 Properties and Function of STP Target Specificity Fast Associative Memories Complex Temporal Filters

18. CS 2016 Determinants of STP Property of terminal (pre- or postsynapse?) Synapses between pyramidal (P) and bitufted (B) or multipolar (M) cells (both interneurones). Same P axon contacting –bitufted cell: facilitation. –multipolar cell: depression. Target-specificity of short-term plasticity: target may determine plasticity. Mechanisms: CB 1 -R? Reyes & Sakmann (1998), Nat Neurosci 1: 279.

19. CS 2016 Fast Associative Memories Fast associative memories (~1 s) formed within networks. Excellent candidate for this type of memory is STP. –Within networks complex time-varying filters arise as a consequence of interactions between facilitation, depression, augmentation, PTP, etc. Feature extraction (decoding…): based on dynamic synapses. –Immediate retention – but not lasting… Features: –Can be contained in neuronal assemblies of few cells. –Many different memory states can be stored independently. Modified from Fusi (2008), Science 319: 1495

20. CS 2016 Take-Home Messages STD is associated with high p. Mechanism for depression involves vesicle depletion and/or autoreceptors. There are at least 3 vesicle pools in each synapse: RRP, RCP and RP. Targets can determine form of plasticity. STP is a likely cellular substrate for fast associative memory. STP forms complex time-varying filters.

21. CS 2016 That’s it folks…