Why is it good that Na+ influx is restricted just to the Nodes of Ranver?
1) Reduces total Na+ influx and thus amount of energy that needs to be expended to restore Na+ balance after AP
2) Reduces changes in extracellular solute concentrations (particularly important in areas of high axonal densities with high firing rates)
How might myelination contribute to neuronal plasticiy?
Neuronal activity increases myelination
Animals in enriched environments have increased white matter, especially in corpus callosum
How does myelination change over one's lifetime?
Myelination does not end at birth, it increases during development and into adulthood
Could contribute to changes in cognitive ability such as language perception
Deficits in appropriate myelination might contribute to mental diseases such as schizophrenia
Where does myelination of a neuron start?
Myelination is usually restricted to the axon
Starts at distal end of axon hillock with "half-node" of Ranvier
Do other parts of the neuron ever get myelinated?
Cell bodies in olfactory bulb
Dendrites, although myelin sheath is very thin
Difference in thickness of myelination in periphery vs. CNS?
Myelinated axons in CNS are thinner because no endoneurium, so can be very closely positioned next to each other
Are all axons in the CNS myelinated?
Parallel fibers in cerebellum not myelinated
Shaffer collateral fibers in hippocampus not myelinated
In general, what do concentric layers of myelin contain?
Cytoplasm (very thin)
Extracellular space (very thin)
Composition of lipid bilayer of myelin
Different from other cell membranes, but all lipids found in myelin also found in other membranes and vice versa
Rich in cerebrosides and other glycosylated lipids
Little protein but most belongs to a few classes (MBP, PLP); other proteins are CNPase, MAG, OMgp
Protein of myelin sheath
Myelin basic protein (MBP): cytoplasmic; majority of myelin protein with PLP
Proteolipid protein (PLP): transmembrane and might hold stacks of membrane together; majority of myelin protein with MBP
2':3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase): enzymatic activity but doesn't appear to have functional significance
Myelin-associated glycoprotein (MAG): cell adhesion factor, myelin-derived axonal growth inhibitor
Oligodendrocyte myelin glycoprotein (OMgp): cell adhesion factor, myelin-derived axonal growth inhibitor
Causes of myelin degeneration
Many different factors
Genetic, environmental, viral, autoimmune
Genetic disorders of brain white matter
Loss of white matter (myelin) and have multiple underlying genetic causes
Can be specific (temporal-occipital in adreno-leukodystrophy (ALD)) or global (Vanishing white matter disease (VWM))
Diagnosis: metabolites in urine or blood, MRI, neurological testing
Regions affected in MS
Multiple foci of myelin loss in spinal cord, optic nerve, cerebellum
How might MMP play a role in MS?
Matrix Metalloproteinases (MMP) may attack basal lamina of capillaries and allow entry of B and T cells (which activate astrocytes, macrophages)
Ultimately, nerve axon itself is damaged, leading to neurodegeneration
Do we know the mutations involved in leukodystrophies?
Yes, but usually no clear link between specific gene or biochemical pathway affected and the loss of white matter
What gene is involved in ALD and how has it been treated?
ABCD1 gene is mutated in ALD, and is a transporter protein that imports very long chain unsaturated fatty acids (VLCF) into the peroxisome to get degraded
In ALD you have accumulation of VLCF because can't get into peroxisome for degradation
Restoring ABCD1 gene in lentivirus in hematopoietic stem cell gene therapy showed stop of progression of disease up to a year and a half in 2 patients
Dietary supplement to treat ALD, but very controversial
Lorenzo's oil contains shorter chain, monounsaturated fatty acids that out-compete biosynthetic machinery so body doesn't synthesize as much VLCF
Potential concequences of reduced myelination
Loss of STDP (spike timing dependent plasticity)
Loss of millisecond precision
Reduced conduction velocity, altered long-range synchronization
Axonal degeneration and secondary inflammation
Reduced transport of presynaptic proteins
Massive, regionalized lesions of white matter
Mainly early childhood onset
Gene codes for peroxisomal transporter proteion called ADLP coded for by ABCD1 gene (multiple mutations: deletions, point mutations)
Accumulate very long chain fatty acids but unclear how this leads to loss of myelin
Hematopoietic stem cell transplantation has promise for therapy
Lorenzo's oil made ALD famous
Multiple sclerosis (MS)
Loss of white matter in many different regions
Brain stem, cerebellum, optic nerve particularly affected
Varies with geography, especially distance from equator (low from equator up to 40; high from 40-60)
Benign, relapsing-remitting, progressive
Treatment mainly slows progression and relapses, targets immune system and MMP
Can axons distal to injury survive?
Axons distal to injury can survive for many days UNLESS they undergo Wallarian Degeneration
Can functional regeneration occur in the mature CNS?
No, because glial cells of the mature CNS present many neuronal growth inhibitors which stop th einitial sprouting of the nerve stump
Also, injury attracts reactive astrocytes which form the glial scar and form mechanical barrier which prevents regeneration
How is infiltration by reactive astrocytes after injury both good and bad?
Good because limits spread of injury
Bad because scar formation prevents regrowth
How might we be able to initiate myelination?
Paper in journal Neuron showed that neuronal activity can (in vitro) initiate myelination by releasing ATP --> ATP acts on astrocytes causing them to release LIG --> LIG promotes myelin production by oligodendrocytes
Potential pathways to overcome inhibition of axon growth in the CNS
1) Block inhibitors of axon growth (nogo, MAG, etc)
2) Olfactory ensheathing cells (OEC)
3) Bypass regeneration by plasticity of network
Protein made by glial cells that prevents axon growth in CNS
Antibodies against Nogo applied to CSF enable regrowth in response to spinal cord injury but controversial whether Nogo-null transgenic animals show increased CNS regeneration
Other proteins that inhibit activity for neuronal outgrowth
Myelin associated glycoprotein (MAG)
Oligodendrocyte myelin glycoprotein (OMgp)
How do nogo, MAG, OMgp inhibit axon growth?
Bind Nogo-receptor (NgR) on neurons --> NgR interacts with NGF-binding protein p75 and activates neuronal signal transduction cascades through kinases to affect actin cytoskeleton
Possibly signal through neuronal gangliosides
Molecular details of neurite outgrowth inhibition not known yet
Olfactory ensheathing cells (OEC)
Olfactory receptor neurons continually generated throughout life of adult animals and are associated with OECs, which are unique population of glial cells with characteristics of both Schwann cells and astrocytes
Located in olfactory epithelium and in olfactory bulb
Ensheath axons of olfactory receptor neurons as they enter bulb and make contact with mitral and periglomerular cells
OECs live at boundary of regeneration-permissive PNS and regeneration-hostile CNS
Cultured OECs shown to ensheath and maybe myelinate axonal processes
Regeneration of CNS shown using OECs in rodents
NG2+ oligodendrocyte precursor cells (OPC)
Mixed neuronal/glial cell population that have stem cell potential for forming oligodendrocytes and astrocytes, and they proliferate
Present throughout grey and white matter
Receive synaptic inputs from non-myelinated axons in grey and white matter
Subset of these cells is electrically excitable (can fire APs)
Potential for ongoing myelination in adult and remyelination in demyelinating disease (endogenous or transplanted)
Remyelination vs. regeneration
Remyelination via stem cell therapy (OPCs?)
Regeneration by overcoming active block (by Nogo, MAG, OMgp)
How do patients with dysfunction of myelination present?
Have both central and peripheral symptoms
Not very specific presentation which is why you need to do MRI
Loss of myelin
Diagnosed mainly by MRI
Many forms with different time courses
Genes, injury, stroke, age, radiation, virus, toxins
MRI shows defined areas of loss (ALD) or multiple demyelination spots (MS)