THE AUSTRALIAN NATIONAL UNIVERSITY

1. THE AUSTRALIAN NATIONAL UNIVERSITY Short-Term Synaptic Plasticity IIChristian StrickerANUMS/JCSMR - ANUChristian.Stricker@anu.edu.auhttp://stricker.jcsmr.anu.edu.au/STP2.pptx

3. Aims The students should • be aware that short-term depression (STD) is associated with a high release probability (p); • recognise mechanism(s) causing STD; • be cognisant of the fact that vesicle recovery is a slow process (~1 s); • know that there are at least 3 different pools of vesicles in the nerve terminal; • know that the target may determine STP; and • grasp that STP forms complex temporal filters.

4. 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. Short-Term Plasticity: Depression • High p neocortical synapse: easy release… • Depression reaches maximum after 300 ms. • Recovery takes longer than 500 ms (~1 s). • At steady-state, recovery rate = rate of depression • STD typically seen at high p synapses.

6. Experimental Set-up

7. Vesicle Depletion and STD • p ~ vesicle pool. • Vesicle depletion causes drop in p. • Recovery slower than stimulus interval (100 ms). • Loss of vesicles faster than replenishment: • Replenishment > 500 ms. • Why so slow? • Priming of vesicles (ready). • Filling of vesicles (vGluT). • Alignment with • exocytoticmachinery. • Ca2+channels. • presynapticgrid.

8. Experimental Evidence • If depletion causes depression, E1 and E2 must be anti-correlated: • Small E2 follows large E1. • Large(r) E2 follows small E1. • 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. Other Mechanisms for STD • Autoreceptors: receptors on terminal sense [transmitter] (feedback): • Glutamatergic: • Ionotropic: NMDA, AMPA, KA. • Metabotropic: Group I– III. • Adenosinergic: • Metabotropic: A1– A3 receptors. • Purinergic: • Ionotropic: P2X1-7 • Metabotropic: P2Y1-15 • Consequence: transmitter release↓ via Ca2+influx↓: • Activation/inactivation kinetics. • Conductance change. • No depression without release (release-dependent depression).

10. Phases during Build-Up of STD • 100 APs at different frequencies. • Plot all E 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. Vesicle Pools Rizzoli & Betz (2005), Nat Rev Neurosci 6: 57-69 • Estimates for hippocampal synapse (boutontype; 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.

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

13. Beyond Simple Depletion For Advanced Students

14. STD without Depletion • Depletion without anti-correlation • E2 is “independent” of E1. • No statistically significant anti-correlation. • STD without (much) release: • Release-independent depression (RID) • Mechanism(s): • Associated with AP: • Within terminal: Activation/inactivation of conductancesat synapse: • Na+, K+, Ca2+. • Before terminal: AP failure to invade terminal.

15. Variable Recovery from STD • Frequency-dependent recovery (FDR): • At higher stimulus frequencies, recovery rate speeds up. • τ↓ at ≥ 10 Hz. • τ50 Hz~ halved (~0.4 s). • Observed at many different synapses. • Ca2+-dependent process. • RID and FDR are correlated. • Mechanism: • Relief from STD (?). Fuhrmannet al. (2004), J Physiol 557: 415-438.

16. Mechanism of RID & FDR Yoon et al. (2007), MolPharmacol 72: 1210-1219. • Most likely mechanism • Gβγ (neuromodulators ?) from GPCRs activation binds to SNARE complex (SNAP-25) and inhibits release: RID. • Gβγ binding to SNAP-25 can be “blocked” by Ca2+, which rises during a burst of APs causing relief from RID: FDR. • Experimental evidence to date • Serotonin: spinal cord (Gi/o) • Alford & Hamm, 2001ff • (Noradrenaline via Gq)

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

18. Determinants of STP • Property of terminal (pre- or postsynapse?) • Neocortical 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 can determine plasticity. • Mechanisms: CB1-R? Reyes & Sakmann (1998), Nat Neurosci 1: 279.

19. Fast Associative Memories Modified from Fusi (2008), Science 319: 1495 • 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 - not lasting… • Features: • Can be contained in neuronal assemblies of few cells. • Many different memory states can be stored independently.

20. 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. That’s it folks…