LECTURE 12: MYELIN AND SALTATORY CONDUCTIONREQUIRED READING: Kandel text, Pgs 22, 81-87

Myelin is an electrical insulator sheath wrapped around axonsMyelin is an electrical insulator sheath wrapped around axonsOligodendrocytesOligodendrocytes produce myelin on CNS axons produce myelin on CNS axons

Schwann cellsSchwann cells produce myelin on PNS axons produce myelin on PNS axonsShort gaps in myelin along axons called Short gaps in myelin along axons called nodes of Ranviernodes of Ranvier

Myelin’s function is to speed action potential propagation down long axonsMyelin’s function is to speed action potential propagation down long axons

MYELIN SHEATH COMPOSED OF MANY LOOPS OF A GLIAL PROCESSMYELIN SHEATH COMPOSED OF MANY LOOPS OF A GLIAL PROCESS

Each oligodendrocyte has severalEach oligodendrocyte has severalprocesses, each of which producesprocesses, each of which producesa myelin sheath on a different axona myelin sheath on a different axon

Schwann cells each form only aSchwann cells each form only asingle myelin sheathsingle myelin sheath

MYELIN SHEATH GENERATED BY CONTINUED MIGRATIONMYELIN SHEATH GENERATED BY CONTINUED MIGRATIONOF PROCESS LEADING EDGE AROUND AXONOF PROCESS LEADING EDGE AROUND AXON

While the leading glial process continues to encircle the axon,While the leading glial process continues to encircle the axon,the earlier-formed loops undergo compactionthe earlier-formed loops undergo compaction

to form the compact myelin sheathto form the compact myelin sheath

MYELINATED FIBERS VIEWED IN CROSS-SECTIONMYELINATED FIBERS VIEWED IN CROSS-SECTION

Low magnificationLow magnificationLight microscopyLight microscopy

High magnificationHigh magnificationelectron microsopyelectron microsopy

Electron microscopy at Electron microscopy at very high magnification very high magnification

reveals alternatingreveals alternatingmajor dense lines andmajor dense lines and

intraperiod linesintraperiod lines

ORGANIZATION OF THE MYELIN REPEAT PERIODORGANIZATION OF THE MYELIN REPEAT PERIOD

PLP is the most abundant protein in CNS myelinPLP is the most abundant protein in CNS myelin

P0 is the most abundant protein in PNS myelinP0 is the most abundant protein in PNS myelin

THE PARANODE IS SITE OF TIGHT AXON-GLIAL ADHESIONSTHE PARANODE IS SITE OF TIGHT AXON-GLIAL ADHESIONS

ROLE OF MYELIN IN FAST ELECTRICAL TRANSMISSIONROLE OF MYELIN IN FAST ELECTRICAL TRANSMISSION

UnmyelinatedUnmyelinatedAxonAxon

(SLOW CONDUCTION)(SLOW CONDUCTION)

MyelinatedMyelinatedAxonAxon

(FAST CONDUCTION)(FAST CONDUCTION)

Action potential at one point along unmyelinated axon produces current that only Action potential at one point along unmyelinated axon produces current that only propagates short distance along axon, since current is diverted through channels propagates short distance along axon, since current is diverted through channels in axon membrane. So action potential can only next occur short distance awayin axon membrane. So action potential can only next occur short distance away

Myelin reduces effective conductance and capacitance of Myelin reduces effective conductance and capacitance of internodal axon membrane. (how???)internodal axon membrane. (how???)

Action potential at node of Ranvier produces current that propagatesAction potential at node of Ranvier produces current that propagates0.5-5 mm to next node of Ranvier, generating next action potential0.5-5 mm to next node of Ranvier, generating next action potential

SODIUM CHANNELS ONLY AT NODESSODIUM CHANNELS ONLY AT NODESAT VERY HIGH DENSITYAT VERY HIGH DENSITY

THIN AXO-GLIAL SPACE AT PARANODE LOOPS CREATES HIGHNODE-INTERNODE PERIAXONAL RESISTANCE WHICHELECTRICALLY ISOLATES INTERNODAL MEMBRANE

Only 20 Angstrom gap betweenmature paranodal loopand axonal membrane

Tight junctions betweenmature loops

Raxial

Rparanode

Raxial

Rparanode

NODE NODEINTERNODEPARANODE PARANODE

SINCE

Rparanode >>>> Raxial & RleakCHARGING OFINTERNODALMEMBRANEVERY SLOW

AND CHANGEIN INTERNODE

VM IS

INSIGNIFICANT

POTASSIUM CHANNEL SHUNT NOT REQUIRED INMOST MATURE MYELINATED AXONS

Myelinated axons conduct action potentials at ~ 50 mm/msec

Total refractory period of nodal sodium channels after inactivationis ~ 5 msec.

Therefore, by the time sodium channels return to rest after an action potential,the spike has propagated 25 cm away

(which is terminated in most cases)

Potassium channel inhibition in mature myelinated fibers does not alter conduction or promote misfiring.

FORMATION OF NODAL, PARANODAL, AND JUXTANODALFORMATION OF NODAL, PARANODAL, AND JUXTANODALPROTEIN CLUSTERS DURING MYELINATIONPROTEIN CLUSTERS DURING MYELINATION

Kv1

Kv1

Sodium channels cluster early at wide immature nodes. As nodes narrow andmature, sodium channel density increases.

Potassium channels cluster later and shift their position. They first appear at nodes,but move to paranode and then juxtaparanode as structure matures.

POTASSIUM CHANNELS ARE OF CONTINUED IMPORTANCE DURING MATURATION OF MYELIN,SINCE ONLY FULLY MATURE FIBERS CONDUCT FAST ENOUGH TO MAKE THEM UNNEEDED.

PERSISTENCE OF POTASSIUM CHANNELS IN MATURE JUXTAPARANODES MAY FUNCTIONALLYPROTECT FIBERS IN CASE OF PARTIAL DE-MYELINATION

MUTATIONS CAN CAUSE MINOR OR MAJOR MYELIN LOSSMUTATIONS CAN CAUSE MINOR OR MAJOR MYELIN LOSS

““SHIVERER” mutant mouse has almostSHIVERER” mutant mouse has almostcomplete absence of myelination,complete absence of myelination,due to a failure of precursor cellsdue to a failure of precursor cells

to differentiate into oligodendrocytesto differentiate into oligodendrocytes

Other mutations which impairOther mutations which impairmyelination are mutations in themyelination are mutations in the

major protein components ofmajor protein components ofthe myelin sheaththe myelin sheath

MUTATIONS IN PLP GENE CAUSING HYPOMYELINATION IN CNSMUTATIONS IN PLP GENE CAUSING HYPOMYELINATION IN CNS

Similarly, structural mutations in PNS myelin protein genesSimilarly, structural mutations in PNS myelin protein genescause defective myelination of the PNScause defective myelination of the PNS