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Magic. Magic. LTP. LTD. High/Correlated activity. Low/uncorrelated activity. High NMDA-R activation. Moderate NMDA-R activation. High Calcium. Moderate Calcium. LTP. LTD. What changes during synaptic plasticity?

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High correlated activity

Magic

Magic

LTP

LTD

High/Correlated

activity

Low/uncorrelated

activity

High NMDA-R

activation

Moderate NMDA-R

activation

High

Calcium

Moderate

Calcium

LTP

LTD


High correlated activity

  • 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?


High correlated activity

What can change during synaptic plasticity?

  • Presynaptic release probability

  • The number of postsynaptic receptors.

  • Properties of postsynaptic receptors


High correlated activity

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


High correlated activity

Probability of failure:

K vesicles, Pr – prob of release



High correlated activity

Nr

Nu

1/τu

Postsynaptic

spine

Are there other possible reasons for change in PPR?



High correlated activity

  • 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


High correlated activity

The story of silent synapses

  • Concepts

  • Minimal stimulation

  • Effect of depolarization on NMDA-R



High correlated activity

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


High correlated activity

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


High correlated activity

Protein Phosphorylation with LTP and LTD

Non-phosphorylated

Phosphorylated

Phosphorylation at s831 and s845 both increase conductance but in different ways


High correlated activity

LTD- dephosphorylation at ser 845 with LTP and LTD

Lee et al. 2000



High correlated activity

Trafficking of Glutamate receptors constitutive and activity dependent.

Activity dependent insertion and removal and its dependence on Phosphorylation



High correlated activity

There are two trafficking pathways: dependent.

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

Magic dependent.

Magic

Dephosphorylation

Phosphorylation

decreased

conductance

decreased

AMPAR number

Increased

conductance

Increased

AMPAR number

LTP

LTD

High/Correlated

activity

Low/uncorrelated

activity

High

Calcium

Moderate

Calcium


High correlated activity

  • The next two topics will be: dependent.

  • 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)


High correlated activity

Here a picture of a spine, with sources and sinks of calcium dependent.

  • Sources

  • NMDAR

  • VGCC

  • Release from internal

  • stores

  • Sinks

  • Diffusion

  • Buffers

  • Pumps


High correlated activity

Calcium through dependent.

NMDAR


High correlated activity

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


High correlated activity

t the GHK equation (See Johnston and Wu pg: )

»

25

ms

Ca

  • 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


High correlated activity

Show calcium transients at low and high postsynatic voltage. the GHK equation (See Johnston and Wu pg: )

Talks about NMDA-R as a coincidence detector


High correlated activity

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

Magic

=


High correlated activity

Summary from Calcium to Phosphorylation/ Dephosphorylation


High correlated activity

  • How can we from Calcium to Phosphorylation/ Dephosphorylation

  • 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?