The structure and function of myelinated nerve

Mark Baker

Neuroscience

• Learning Objectives (all knowledge based):

• Provide an explanation of how impulses are propagated

• Describe how myelin works

Resting potentials and action potentials

10 mM Na+ 140 mM Na+

120 mM K+

2 mM K+

Inside Outside

K+ channels

Na+ channel

10 mM Na+ 140 mM Na+

120 mM K+

2 mM K+

+ve

+ve

Inside Outside

-ve

Na+ channel

K+ channels

10 mM Na+ 140 mM Na+

120 mM K+

2 mM K+

Inside Outside

-80 mV

Na+ channel

K+ channels

10 mM Na+ 140 mM Na+

120 mM K+

2 mM K+

Inside Outside

-80 mV

Na+ channel

K+ channels

• Reversal potential (E) for an ion is given by the Nernst equation:

• At 20 ºC, 58.2 log [out]/[in]

• At 37 ºC, 61.5 log [out]/[in]

• Thus a normal value of EK is negative and ENa is positive

Na+ current generates up-swing of action potential

Na+ channel inactivationand K+ channel activationunderlie repolarization

K+ channel activationgenerates afterhyperpolarization

Function of myelinated nerve

nerve conducts action potentials by local circuit currents

Function of myelinated nerve

node of Ranvier

internode

outside

inside

direction of impulse

optic nerve axons (Brady et al 1999)

compact myelin

Shiverer mouse(myelin basic protein null)

local circuit current

potentialsrecordedextracellularly

axon

longitudinal currents

transmembranecurrent

Tasaki 1959

air gaps

R R

nodesingle fibreteased out

current across the myelin

0 1 2 ms-2

0

2cu

rren

t (n

A)

transmembrane current at a node

0 1 2 ms -2

0

curr

ent

(nA

)

2

Function of myelinated nerve

internode

Tasaki 1959

air gaps

R R

nodesingle fibreteased out

current across the myelin

0 1 2 ms-2

0

2cu

rren

t (n

A)

transmembrane current at a node

0 1 2 ms -2

0

curr

ent

(nA

)

2

Function of myelinated nerve

inward current

outward current

internode

• Function of myelinated nerve

Conduction velocity in a large myelinated axon is around 50 ms-1.

An action potential at a single point lasts close to 0.5 milliseconds at body temperature.

Therefore the action potential is around 25 mm (an inch) long.

If there are nodes at 1 mm intervals, over 20 will be involved simultaneously in propagating a single impulse.

-80

+40

me

mb

ran

e p

ote

ntia

l (m

V)

5 ms

stimulator

A

B

depolarizing afterpotential (DAP)

• Function of myelinated nerve

action potentialIn the mammal repolarization occurswithout K+ channel involvement (shown by Chu et al 1979)

H1

(cartoons only)

(real thing!!)

from Barrett EF and Barrett JN (1982)

DAP

• S.Y. Chiu, J.M. Ritchie, R.B. Rogart and D. Stagg, 1979

• Function of myelinated nerve

Why worry about the DAP – just a detail isn’t it??

• DAP is functionally important because a myelinated axon is easier to stimulate during the residual depolarization (following the refractory period). The DAP contributes to repetitive firing and sensory coding

• What is the process that allows repolarization of a node following an action potential? This has been a puzzle because kinetically fast delayed rectifier K+ channels are not found at adult mammalian nodes of Ranvier. Problem solved by Barrett and Barrett 1982 – DAP is a part of the answer.

• Turns out if you know how the DAP is generated –you understand how the axon works.

Explain what electrical capacity is!!

+

-

R

C

Explain what electrical capacity is!!

+

-C

R

+

-time

V = RC

Explain what electrical capacity is!!

+

-C

R

+

-time

V = RC

time

I

initially behaves like a closed circuit,current flow determined by value of the resistor

finally behaves like an open circuit, there is no current flow in the circuit at all

What is the potential drop across the capacitor when it has fullycharged, and the current in the circuit has dropped to zero?

• Biological membranes provide large capacities (microscopic lipid bilayer with conducting solution on either side) usually taken to be 1Fcm-2.

• Internodal membrane provides a capacity about 1000 times more than a node of Ranvier, so this will short-circuit the action currents close to the nodes, unless steps are taken to prevent it.

100 pF capacitor

(p pico, 10-12 ; SI nomenclature)

In parallel, what is the total capacty?

In series, what is the total capacty?

Axolemma

Periaxonal space

Myelin

Myelinlow capacitance-1/Ctotal = 1/C1+1/C2 +…. 1/Cn

Axolemma large capacitance

Barrett and Barrett resistance, makes myelina poor insulator because there are current pathways across it. Without it, the node couldn’t repolarize, and theaxon would not have a resting potential

• Myelin provides a low capacity sheath – membrane stack has a much reduced capacity (like separating the two plates of a capacitor)

• The single internodal axon membrane (under the myelin) has a high capacity, so that action currents go straight through it – as though invisible, generating only a small change in potential across the membrane, the DAP

• If the myelin were a good insulator the axon simply wouldn’t work, because it would not have a resting potential, and the action potential at the node couldn’t repolarize!!!

Numerical simulation run at room temperature, Baker 2000

getting the model right

• Function of myelinated nerve

Barrett and Barrett (1982) got the model right

Summary of function

• Myelinated nerve is a remarkable structure designed to efficiently propagate impulses at high speed.

• Ion channels and other proteins are targeted to discreet regions of axonal membrane in the formation of nodes and internodes.

• Only nodes are electrically excitable.• The myelin sheath provides low internodal

capacitance to allow energy efficient transmission, but is a relatively poor insulator, allowing internodal K+ channels to set the axonal membrane potential.

Structure of myelinated nerve

• Learning Objectives (all knowledge based):

• Be able to describe the basic structure of myelinated nerve.

• Be aware of the distribution of ion channels and cell-adhesion molecules that helps define distinct domains along an axon, and stabilizes the sheath

• In the PNS Schwann cells engulph axons, and where the axon is greater than 1-2 m in diameter, the Schwann cell forms a myelin sheath around it. Axons are ensheathed sequentially by single Schwann cells.

• Schwann cells produce basement membrane that includes laminin a matrix protein that is essential for normal nerve development, function and regeneration.

From Poliak and Peles 2003

Oligodendrocyte

Astrocyte foot process

In the central nervous system,

oligodendrocytes ensheathe

several axons. Axons as small

as 0.2 m in diameter are

myelinated. Oligo’s can produce

Myelin that spirals in oposite

directions

Astrocytic foot processes

contact nodes.

Construction of myelinated nerve

Myelinating cells cause clustering of Na+ and K+

channelsand induce large axonal diameters

Na+ channels (green) Caspr 1 (red)Fast K+ channels (blue)

rat optic nerve

10 M

Matthew Rasband and Peter Shrager 2000

Rudolf Martini

Peter Shrager

Formation of nodes of Ranvierby Schwann cells

-subunits interact with both intracellular and extracellular proteins, controlling Na+ channel localization and contributing to the control of

channel density

1 is crucial

tenascin-R

ankyrin-G

Nf186contactin

1

2

Axon membrane

Oligodendrocyte

spectrin,actin cytoskeleton

Ig-CAMs

(lectin-likedomains)

-subunit

McEwen j. Biol Chem 279: 16044-16049 (2004)

D.P. Schafer and

M. N. Rasband (2006)

Glial CAMs recruitaxonal CAMs at points of contact

Axonal CAMsare attachment sites for cyto-skeletal proteins

Copyright ©2002 Society for Neuroscience

Arroyo, E. J. et al. J. Neurosci. 2002;22:1726-1737

Figure 10.

• Myelin structure

Myelin protein P0 is a cell adhesion molecule in Schwann cells

extracellular membranes

Scherer and Arroyo 2002

EM of compact myelin interpretation

Summary of structure• Myelinating cells in CNS and PNS differ

• Axon-satellite cell interaction is crucial for the formation of nodes of Ranvier e.g interaction of gliomedin in Schwann cells and NF186 is an important factor in Na+ channel clustering

• Myelinated axon membrane incorporates domains typically expressing certain ion channels and cell adhesion molecules (CAMs)

• Sheath contains characteristic CAMs eg P0, and these stabilize myelin

ReferencesStructure of myelinated nerve eg:

L. Shapiro et al (1996) Neuron 17: 435-449 (crystal structure of P0)

M. Rasband and P. Shrager (2000) Ion channel sequestration in central nervous system axons. J Physiol. 525:63-73.

E.J. Arroyo et al. (2002) Genetic dismyelination alters nodal structure J. Neurosci. 22:1726-1737

Y. Eshed et al. (2005) Neuron 47: 215-229 Giomedin mediates Schwann cell-axon interaction and the assembly of nodes of Ranvier

Scherer and Arroyo (2002) Recent progress on the molecular organization of myelinated axons J Peripher Nerv Syst. 7:1-12 (Review)

Poliak and Peles (2003) The local differentiation of myelinated axons at nodes of Ranvier. Nat Rev Neurosci. 4:968-80 (Review)

D.P. Schafer and M.N. Rasband (2006) Current opinion in Neurobiology 16: 508-514. (Review) READ THIS

References

Function of myelinated nerve eg:

Try: M.D. Baker (2000) Trends in Neuroscience 23: 514-519

Chiu SY, Ritchie JM, Rogart RB and Stagg D (1979) A quantitative description of membrane currents in rabbit myelinated nerve. J Physiol. Jul;292:149-66

Barrett EF and Barrett JN (1982) Intracellular recording from vertebrate myelinated axons: mechanism of the depolarizing afterpotential. J Physiol. 1982 Feb;323:117-44.