High/Correlated activity HighCalcium LTP Low/uncorrelated activity Moderate Calcium Calcium LTD LTD Magic High NMDA-R activation Moderate NMDA-R activation

What changes during the expression of synaptic plasticity? Is expression pre or post-synaptic What are the mechanisms leading from induction to expression

Presynaptic release probability The number of postsynaptic receptors. Properties of postsynaptic receptors What can change during synaptic plasticity?

A single mini Induced release is multi-quantal

Statistics of the quantal hypothesis: N available vesicles P r - prob. Of release Binomial statistics:

N available vesicles P r - prob. Of release Binomial statistics: Examples mean: variance: Note – in real data, the variance is larger

Possible evidence for a pre-synaptic mechanism 1. Change in failure rate (minimal stimulation) Probability of failure: N vesicles, P r – prob of release

2. Change in coefficient of variation CV Assume a synapse with N vesicles available for release each with a probability of release P r and each vesicle released causes a postsynaptic response with magnitude μ. The mean response is: The variance is: The CV 2 (variance/mean 2 ) is:

Plot on matlab CV 2 vs P r and vs. N:

Short term synaptic dynamics: depression facilitation 3. Change in paired pulse ratio (PPR)

Synaptic depression: N r - vesicles available for release. P r - probability of release. Upon a release event N r P r of the vesicles are moved to another pool, not immediately available (N u ). Used vesicles are recycled back to available pool, with a time constant τ u

Therefore: And for many AP’s: NuNu NrNr 1/τ u

Show examples of short term depression. How might facilitation work?

NuNu NrNr 1/τ u Are there other possible reasons for change in PPR? Postsynaptic spine

4. Open channel blocker MK-801

Evidence for postsynaptic change: 1.No change in failures 2.No change in CV 3.No change in PPR 4.No change in MK Change in the magnitude of successful transmission 6.No change in NMDA-R component

The story of silent synapses before after

The story of silent synapses Concepts Minimal stimulation Effect of depolarization on NMDA-R

Model of synaptic plasticity

Mechanisms for the induction of synaptic plasticity Phosphorylation of receptors Phosphatases, Kinases and Calcium How do we model the Phosphorylation cycle Receptor trafficking Receptor trafficking and Phosphorylation

Phosphorylation state of Gultamate receptors is correlated with LTP and LTD GluR1-4, functional units are heteromers, probably composed of 4 subunits, probably composes of different subtypes. Many are composed of GluR1 and GluR2 R2 R1 P P

Protein Phosphorylation Non-phosphorylatedPhosphorylated Phosphorylation at s831 and s845 both increase conductance but in different ways

LTD- dephosphorylation at ser 845 Lee et al. 2000

LTP- phosphorylation at ser 831

Trafficking of Glutamate receptors constitutive and activity dependent. Activity dependent insertion and removal and its dependence on Phosphorylation

Malinow, Malenka 2002

There are two trafficking pathways: 1- Short, in which there is constant plasticity independent trafficking. But dephosphorylation at ser 880 on GluR2 might still trigger LTD. 2- Long, in which phosphorylation triggers LTP. Note – Phosphorylation also increases conductance directly

High/Correlated activity HighCalcium LTP Phosphorylation Increased conductance Increased AMPAR number Low/uncorrelated activity Moderate Calcium Calcium LTD Dephosphorylation decreasedconductancedecreased AMPAR number Magic