LECTURE 12: MYELIN AND SALTATORY CONDUCTION

1. LECTURE 12: MYELIN AND SALTATORY CONDUCTION REQUIRED READING: Kandel text, Pgs 22, 81-87 Myelin is an electrical insulator sheath wrapped around axons Oligodendrocytes produce myelin on CNS axons Schwann cells produce myelin on PNS axons Short gaps in myelin along axons called nodes of Ranvier Myelin’s function is to speed action potential propagation down long axons

2. MYELIN SHEATH COMPOSED OF MANY LOOPS OF A GLIAL PROCESS Each oligodendrocyte has several processes, each of which produces a myelin sheath on a different axon Schwann cells each form only a single myelin sheath

3. MYELIN SHEATH GENERATED BY CONTINUED MIGRATION OF PROCESS LEADING EDGE AROUND AXON While the leading glial process continues to encircle the axon, the earlier-formed loops undergo compaction to form the compact myelin sheath

4. MYELINATED FIBERS VIEWED IN CROSS-SECTION Low magnification Light microscopy High magnification electron microsopy Electron microscopy at very high magnification reveals alternating major dense lines and intraperiod lines

5. ORGANIZATION OF THE MYELIN REPEAT PERIOD PLP is the most abundant protein in CNS myelin P0 is the most abundant protein in PNS myelin

6. THE PARANODE IS SITE OF TIGHT AXON-GLIAL ADHESIONS

7. ROLE OF MYELIN IN FAST ELECTRICAL TRANSMISSION Unmyelinated Axon (SLOW CONDUCTION) Myelinated Axon (FAST CONDUCTION) SODIUM CHANNELS ONLY AT NODES AT VERY HIGH DENSITY Action potential at one point along unmyelinated axon produces current that only propagates short distance along axon, since current is diverted through channels in axon membrane. So action potential can only next occur short distance away Myelin reduces effective conductance and capacitance of internodal axon membrane. (how???) Action potential at node of Ranvier produces current that propagates 0.5-5 mm to next node of Ranvier, generating next action potential

8. THIN AXO-GLIAL SPACE AT PARANODE LOOPS CREATES HIGH NODE-INTERNODE PERIAXONAL RESISTANCE WHICH ELECTRICALLY ISOLATES INTERNODAL MEMBRANE Tight junctions between mature loops Only 20 Angstrom gap between mature paranodal loop and axonal membrane SINCE Rparanode >>>> Raxial & Rleak CHARGING OF INTERNODAL MEMBRANE VERY SLOW AND CHANGE IN INTERNODE VM IS INSIGNIFICANT Rparanode Rparanode Raxial Raxial NODE PARANODE INTERNODE PARANODE NODE

9. POTASSIUM CHANNEL SHUNT NOT REQUIRED IN MOST MATURE MYELINATED AXONS Myelinated axons conduct action potentials at ~ 50 mm/msec Total refractory period of nodal sodium channels after inactivation is ~ 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.

10. FORMATION OF NODAL, PARANODAL, AND JUXTANODAL PROTEIN CLUSTERS DURING MYELINATION Kv1 Kv1 Sodium channels cluster early at wide immature nodes. As nodes narrow and mature, 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 FUNCTIONALLY PROTECT FIBERS IN CASE OF PARTIAL DE-MYELINATION

11. MUTATIONS CAN CAUSE MINOR OR MAJOR MYELIN LOSS “SHIVERER” mutant mouse has almost complete absence of myelination, due to a failure of precursor cells to differentiate into oligodendrocytes Other mutations which impair myelination are mutations in the major protein components of the myelin sheath

12. MUTATIONS IN PLP GENE CAUSING HYPOMYELINATION IN CNS Similarly, structural mutations in PNS myelin protein genes cause defective myelination of the PNS