1. Synapse III- short term plasticity and other advanced topics

2. Short term plasticity Following a single impulse or an impulse train, the postsynaptic response to an impulse can be depressed, facilitated or modulated by G protein Why is short term plasticity important? “On rapid timescales (milliseconds to minutes) the release of neurotransmitter depends on the pattern of presynaptic activity, and synapses can be thought of as filters with distinctive properties. This provides synapses with computational potential and has important implications for the diversity of signaling within neural circuits“ (Abbott 2004).

3. Types Timescale of milliseconds- depression/ facilitation. Timescale of seconds-minutes- post synaptic augmentation/potentiation

4. Short term plasticity-depression Depression: Repetitive activity results in a decreased amplitude of postsynaptic responses Occurs within 10s of msecs Dissipates within seconds In synapse with high Prelease Post tetanic depression Develops over seconds Slowly decays, tens of seconds

5. pre-synaptic effect due to decrease in m (m= N*P, quantal content). The most widespread mechanism appears to be a presynaptic decrease in N- (smaller Ready Releasable Pool), due to depletion of a release-ready pool of vesicles or a change in secretion mediated by specific signals) sometime also a decrease in P(release) through changing Ca, Ca sensitivity… Postsynaptic properties such as desensitization of ligand-gated receptors can also make the target neuron less sensitive to neurotransmitter. Synaptic depression

6. Not only Ca deficiency Sakaba 2004

7. But not only depletion either Increasing /Ca results in lager first release (more vesicles) but size of depression was uneffected  it can’t be only depletion. Sullivan 2006

9. Depression- mechanisms (summary) Due to either decrease in Ca, depletion of readily releasable pool of vesicles or post synaptic desensitization All mechanisms can be constantly or transient present Schnegenburger 2002

10. A key characteristic of depression at many synapses is its use dependence. Higher levels of transmission are associated with larger depression, and reduction of baseline transmission (for example by reducing external [Ca]), relieves depression. Depression is dynamic- less in case of spontaneous activity then in silent. Reigh 2006

11. Implications- Depression 1.High Pr, then decrease- response to stimulus onset. 2.Sensitivity to broad range of sound intensities (depression as homeostating tool). 3.Sensitivity to pre-post coherence in firing rate, not the mean. Generally- high Pr- high pass filter, low Pr, low pass filter Abbot 2004 Example- adaptation to whisker stimulation due to depression in thalamus-cortex connection Different filtering

12. Facilitation Repetitive activity that results in an enhanced amplitude of a postsynaptic response Occurs within 10s of msec Dissipates within seconds In neurons with low probability of release synapses 20 msec 100 pA Post tetanic Potentiation Develops over seconds Slowly Decays (tens of seconds to minutes) Low P release,

13. Synaptic facilitation causes In all synapses studied, facilitation, augmentation, and PTP have all been shown by quantal analysis to be presynaptic in origin— to involve specifically an increase in the number of transmitter quanta released by an AP without any change in quantal size or postsynaptic effectiveness. pre-synaptic effect due to increase in m by raising p, Caused by residual Ca +2 over loading from ER reservoirs or retrograde signaling 0

14. The Residual Ca2+ Hypothesis “residual Ca hypothesis”: Facilitation is caused by an action of Ca remaining in the nerve terminals after the conditioning stimulus. Evidences: correlation between elevations in Ca and synaptic enhancement elevating Ca enhances synaptic strength preventing increases in Ca eliminates short-term facilitation. Preventing proximity between Ca channels and vesicle prevented facilitation( kittel 2006)

15. What regulates the duration of residual calcium Kinetics of pumps which expel calcium from cell Kinetics of uptake of calcium into internal stores Calcium release from intracellular stores Calcium for channels- (in shaffer collateral-prolong pre synaptic firing activate also L type Ca channel with slower kinetics and therefore longer Ca entry- Jensen 2001)

16. Post-Tetanic Potentiation There are also processes that become increasingly important as the number of stimuli in a train is increased. For these processes, each AP enhances synaptic strength by 1–15%, but because they last for five seconds to several minutes, the integrated effect of a train of hundreds of pulses can lead to a many-fold enhancement.

17. Activation of plasticity retrograde messengers that regulate neurotransmitter release: Most common- The endocannabinoid system- They are released from the postsynaptic cell following the cleavage of lipid precursors (due to Ca increase or a second messenger system); They lead to an inhibition of neurotransmitter release that lasts for tens of seconds. The roles of retrograde inhibition by endocannabinoids are not yet well understood. Possibly for homeostatic purposes. Another example- dendritic post synaptic release of glutamate to pre synaptic kainate (Glutamate) receptor causes Pr increase

18. Another source-Regulation by G-Proteins. Many chemical messengers can act as ligands for G-protein –coupled receptors: GABA,Adenosine,Glutamate, Dopamine, Serotonin. Target is typically Ca2+ or K+ channels Binding of G  puts a Ca 2+ channel into a reluctant state, with a reduced open probability. Inhibition by G protein G-Protein-Mediated Autoinhibition Transmitter molecules released in a synapse may bind to G protein- coupled receptors presynaptically, inhibiting Ca2+ channels and reducing future transmitter release. EPSCs from dopamine synapses in the striatum. S1 is a train of 3 impulses at 100 Hz. S2 is a single impulse 200 ms later.. In many cases, G protein channel inhibition can be relieved by depolarization There are 55 known G  dimeric isoforms with different effects.

19. Copyright ©1998 by the National Academy of Sciences Differential synaptic facilitation and depression via the same axon innervating two different targets Markram 1998 Same as different P(release) for different target cells

20. For example, Naschtalagger 2005 suggested that release is optimized for maximal summation of EPSP in the post synaptic cell. Natschläger T, Maass W.(2000)

21. Sites of Regulation of Short-term Plasticity Action potential waveform Ca 2+ channel activation Readily releasable pool Reserve pool of vesicles autoreceptors Ca-ATPase, regulation residual [Ca] i Mitochondrial regulation of [Ca] i Postsynaptic receptor desensitization Decreased driving force Adapted from Zucker & Regehr, 2002 Presynaptic Postsynaptic Extrasynaptic Glial uptake of neurotransmitter Other mechanisms?