Synaptic plasticity: Introduction

• Different induction protocols

• Basic properties

• Key elements of the biophysics

• Site of change: pre or post-synaptic

• More on Mechanism

•

Rate based induction(show on board)

But: Heterosynaptic LTD – from Abraham(note – in vivo)

Note about the different meanings of hetero

Christie et. Al 1995

Pairing induced plasticity

Feldman, 2000

Show voltage clamp

Spike timing dependent plasticity

Markram et. al. 1997

Anatomy figure from Markram 97

Spike timing dependent plasticity

Markram et. al. 1997

Bi and Poo J. Neurosci. 1998

Some properties (observations) of synaptic plasticity

• Synapse specificity (but)

• Associatively (pre and post occur together)

• Cooperativety (two different input pathways can boost each other)

1. Voltage dependence

2. Calcium permeability

Some key elements of the biophysics of induction

1. NMDA receptors are necessary (in many systems) for the induction of LTP and LTD

Bi and Poo, 1998

Control

With APV

Same hold for LTD – but some forms of plasticity are NMDAR independent

Partial blockade of NMDA-R

Cummings et. al , 1996

2. Calcium influx is necessary for plasticity

and its level determines the sign and magnitude of plasticity

And might be sufficient

Yang, Tang Zucker, 1999

• Moderate, but prolonged calcium elevation = LTD

• High calcium elevation = LTP ( brief is sufficient, but what will long do? )

Yang, Tang Zucker, 1999

High/Correlated activity

High High CalciumCalcium

LTP

LTP

Low/uncorrelated activity

ModerateModerate CalciumCalcium

LTD

LTDLTD

Magic Magic

High NMDA-Ractivation

Modelrate NMDA-Ractivation

• 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?

• Presynaptic release probability

• The number of postsynaptic receptors.

• Properties of postsynaptic receptors

What can change during synaptic plasticity?

Possible evidence for a presynaptic mechanism

1. 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

Evidence for postsynaptic change:

1.No change in failures2.No change in PPR3.No change in NMDA-R component4.Different change for AMPA and NMDA-R currents5.No change in MK-801

Are there other possible reasons for change in PPR?

The story of silent synapses

Concepts• Minimal stimulation• Effect of depolarization on NMDA-R

Model of synaptic plasticity

Summary – up to here.

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

R1

R2

R2

R1P

P

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

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

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

Sources• NMDAR• VGCC• Release from internal stores

Sinks • Diffusion• Buffers• Pumps

Calcium throughNMDAR

1)13.16/exp(

57.3

][1

2

VmM

MgGNMDA

1)13.16/exp(

57.3

][1)(

2

VmM

MgVG

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

)())(( GluCarNMDACa ttFVVVGgj

• Ligand binding kinetics – sum of two exponentials with different time constants (Carmignoto and Vicini, 1992)

• Calcium Dynamics- first order ODE

CaiCa

i ICadt

Cad ][

1][

0.7

0.5

0.0

NMDA receptor kinetics- sum of two exponents

msCa 25

Show calcium transients at low and high postsynatic voltage.

Talks about NMDA-R as a coincidence detector

Magic

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

=