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

What changes during synaptic plasticity? What is the mechanism responsible for the induction of synaptic plasticity? (magic?) Can every form of plasticity be accounted for by STDP? What are the rules governing synaptic plasticity? How is synaptic plasticity maintained?

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

Possible evidence for a presynaptic mechanism Change in failure rate (minimal stimulation) 2. Change in paired pulse ratio (explain on board – for both ppf and ppd) 3. The MK 801 test

Probability of failure: K vesicles, Pr – prob of release

Reminder: short term synaptic dynamics: depression facilitation

Are there other possible reasons for change in PPR? Nu Nr 1/τu Postsynaptic spine Are there other possible reasons for change in PPR?

What would happen when we have PPF?

Evidence for postsynaptic change: No change in failures No change in PPR No change in NMDA-R component Different change for AMPA and NMDA-R currents No change in MK-801

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

Many are composed of GluR1 and GluR2 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 P R1 R1 P R2

Protein Phosphorylation Non-phosphorylated Phosphorylated 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

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

The next two topics will be: From activity to calcium “Magic” – from calcium to phosphorylation: the signal transduction pathways Keep in mind, as complex as it might seem to you, it is actually much more complex. This is a cartoon version, passed through my subjective filters (the end)

Here a picture of a spine, with sources and sinks of calcium NMDAR VGCC Release from internal stores Sinks Diffusion Buffers Pumps

Calcium through NMDAR

For calcium channels the more precise formulation is to use the GHK equation (See Johnston and Wu pg: ) However, for simplicity we will use the simple ‘Ohmic’ formulation: jCa

Ligand binding kinetics – sum of two exponentials with different time constants (Carmignoto and Vicini, 1992) Calcium Dynamics- first order ODE NMDA receptor kinetics- sum of two exponents 0.7 0.5 0.0 ms Ca 25 » t

Show calcium transients at low and high postsynatic voltage. Talks about NMDA-R as a coincidence detector

A brief summary of the signal transduction pathway leading from Calcium to Phosphorylation/ Dephosphorylation Magic =

Summary

How can we Model the activation of different kinases and phosphatases mathematically? How can we model phosphorlation and dephophorylation by these enzymes? Do we have any hope of modeling such a complex system? Is there a simpler way?