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Transcript of 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