high/correlated activity highcalcium ltp low/uncorrelated activity moderate calcium calcium ltd ltd...

High/Correlated activity

High High CalciumCalcium

LTP

LTP

Low/uncorrelated activity

ModerateModerate CalciumCalcium

LTD

LTDLTD

Magic Magic

High NMDA-Ractivation

Moderate NMDA-Ractivation

• 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•Pr- prob. Of release

Binomial statistics:

K

NKNr

Kr PPNKP )1()()|(

•N available vesicles•Pr- prob. Of release

Binomial statistics: Examples

K

NKr

Kr PPNKP )1()()|(

mean:

variance:

NPK r

)1(2rr PPN

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, Pr – prob of release

NrPfailureP )1()(

2. Change in coefficient of variation CV

Assume a synapse with N vesicles available for release each with a probability of release Pr and each vesicle released causes a postsynaptic response with magnitude μ.

The mean response is:

The variance is:

The CV2 (variance/mean2 ) is:

rPN

)1(2rr PPN

r

r

r

rr

PN

P

PN

PPNCV

1)1(222

22

Plot on matlab CV2 vs Pr and vs. N:

Short term synaptic dynamics:

depression facilitation

3. Change in paired pulse ratio (PPR)

Synaptic depression:

• Nr- vesicles available for release.

• Pr- probability of release.• Upon a release event NrPr of the vesicles are

moved to another pool, not immediately available (Nu).

• Used vesicles are recycled back to available pool, with a time constant τu

Tru

uuirrr

NNN

NttNPdt

dN

/)(

urTirrr NNttNP

dt

dN /)()(

Therefore:

And for many AP’s:

urTii

rrr NNttNP

dt

dN /)()(

NuNr

1/τu

Show examples of short term depression.

How might facilitation work?

urTii

rrr NNttNP

dt

dN /)()(

NuNr

1/τu

Are there other possible reasons for change in PPR?

Postsynapticspine

4. Open channel blocker MK-801

Evidence for postsynaptic change:

1.No change in failures2.No change in CV3.No change in PPR4.No change in MK-801

5.Change in the magnitude of successful transmission6.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

R2

R1 P

P

R1

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

High/Correlated activity

High High CalciumCalcium

LTP

PhosphorylationPhosphorylation

Increasedconductance

Increased AMPAR number

Low/uncorrelated activity

ModerateModerate CalciumCalcium

LTD

Dephosphorylation

decreaseddecreasedconductanceconductance

decreased decreased AMPAR numberAMPAR number

Magic Magic