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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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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?

  • 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



Nr

Nu

1/τu

Postsynaptic

spine

Are there other possible reasons for change in PPR?



  • 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



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

P

R1

R1

P

R2


Protein Phosphorylation with LTP and LTD

Non-phosphorylated

Phosphorylated

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


LTD- dephosphorylation at ser 845 with LTP and LTD

Lee et al. 2000



Trafficking of Glutamate receptors constitutive and activity dependent.

Activity dependent insertion and removal and its dependence on Phosphorylation



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


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


  • 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)


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

  • Sources

  • NMDAR

  • VGCC

  • Release from internal

  • stores

  • Sinks

  • Diffusion

  • Buffers

  • Pumps


Calcium through dependent.

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


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


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


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

Magic

=


Summary from Calcium to Phosphorylation/ Dephosphorylation


  • 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?


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