Myelination in CNS (Week 3--Schweizer) Flashcards Preview

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Flashcards in Myelination in CNS (Week 3--Schweizer) Deck (33)
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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?

Lipid bilayer

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

Few phospholipids

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


Lorenzo's oil

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

Conduction blocks

Abnormal sprouting

Axonal degeneration and secondary inflammation

Reduced transport of presynaptic proteins


Adreno-leukodystrophy (ALD)

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)

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