Lecture #11 Flashcards

1
Q

describe the similarities between schwann cells and oligodendrocytes:

A
  • involved in the formation of the myelin sheath
  • present during embryonic and post-natal life
  • can wrap along the axon
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2
Q

what oversees the formation of the myelin sheath and wrapping of the axon in the periphery?

A

Schwann cells

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3
Q

what oversees the formation of the myelin sheath and the wrapping of the axon in the CNS?

A

oligodendrocytes

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4
Q

where are Schwann cells derive from?

A

the neural crest - soon after the closure of the neuronal tube they migrate to the dorsal tip

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5
Q

where are oligodendrocytes generated from?

A

the same progenitors as neurons in the CNS → neuroepithelial cells at the beginning that will later change to microglial cells

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6
Q

how much does myelination increase the propagation?

A

10 fold - creates a saltatory connection: action potential jumps from one node of Ranvier to the next

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7
Q

what is myelin?

A

a fatty insulating wrap that facilitates the saltatory conduction of action potentials

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8
Q

describe the resistance and capacitance of myelin, and how this contributes to its function:

A

resistance is high and capacitance is low → there is the movement of chargers from the axon shaft to the external environment in the region wrapped with myelin

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9
Q

what is the region lying between two myelin sheaths called?

A

internal region

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10
Q

what is the juxtaparanodal region?

A

the region near the node where the myelin sheath starts to change and become less compact

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11
Q

why is myelin tightly packed?

A

in the nodal region, the shaft is in functional contact with the extracellular space and therefore the Na can flux from the extracellular space to the cytoplasm when the ion channel starts to open

flanking these regions you have K channels that are important for the falling of the action potential

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12
Q

why is the electrical resistance high but the capacitance low?

A

electrical resistance is high because the ions are not able to cross the lipid layer, and the capacitance is low because the space between the shaft and the extracellular medium is big compared to the small space when the membrane is free

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13
Q

describe the amount of Schwann cells vs the amount of oligodendrocytes:

A

1:1 ratio of Schwann cells (SC to axon) and a 1:5-1:30 ratio of oligodendrocytes

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14
Q

what represents 70% of myelin’s dry weight, and what is the most represented type?

A

lipids → the coat that you need to insulate the axon

cholesterol is the most represented

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15
Q

what is the function of the lipid component of myelin?

A

provide insulation while the proteins fuse and stabilize the lamella during the wrapping process

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16
Q

what are the two main proteins that are specific to myelin?

A

myelin basic protein (MBP) and proteolipid protein (PLP)

comprise 80% of the CNS proteins

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17
Q

what is the transgenic mice model used to investigate myelination with mutations in MBP?

A

shiverer

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18
Q

describe shiverer mice:

A

the oligodendrocytes in the CNS cannot wrap the myelin and the mice have tremors - they do not survive long and are useful for studies in remyelination in adults

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19
Q

what is the very rare, but important oligodendrocyte protein, and what is its function?

A

myelin oligodendrocyte glycoprotein (MOG) → a specific small peptide belonging to the central part of MOG is used to generate one of the most famous animal models for inflammatory disorders

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20
Q

what other family of proteins is present and allows water and ions to move between the leaflets of myelin?

A

connexions

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21
Q

what occurs if connexions are absent?

A

there is no movement of molecules between the leaflets as they are compact, and the cytoplasm is non-existent making the movement of molecules difficult

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22
Q

what make oligodendrocytes unique?

A

they are the biggest cells we have

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23
Q

where is the cytoplasm located in oligodendrocytes?

A

the vast majority is squeezed into the region the nucleus, while in the leaflets there is no cytoplasm whatsoever or it is very scarce

24
Q

what can the oligodendrocyte myelination process be compared to?

A

a balloon inflating

25
Q

describe the oligodendrocyte myelination process of an axon:

A
  • in the initial step there is the axon, two cell membranes, and the cytoplasm
  • the air starts to migrate to the cytoplasm
  • the two membranes collapse and the air is squeezed out forming the first wrap
  • the two membranes start to enter in close contact an the cytoplasm gets squeezed out resulting in almost total elimination
  • the two leaflets start to enter in contact and wrap agin multiple times to form the myelin sheath
26
Q

what do connexins allow for?

A

the possibility for the small molecules to move along the myelin when it is wrapped

27
Q

what three proteins are classical associated to the myelin of the internode?

A

MBP, PLP, and CLP

28
Q

what two proteins are in the juxtaparanode region where the K channels are located?

A

MOG and MAG

29
Q

which proteins are located in the paranode?

A

only MAG - since there is no myelin in the node there are no myelin-related proteins

30
Q

how do Schwann cells enter into contact with the embryo in the periphery?

A

enter into contact with the single shaft and start to wire and produce the classical myelination of the axon

some small calibre axons only enter in contact with specific subsets of Schwann cells, and they engulf the axon but because they cannot make the wrapping these axons are naked

31
Q

what are the naked axons in the periphery called?

A

Remak cells

no myelination = conduction not saltatory

32
Q

what are the function of Remak cells?

A

offer tropic support to the shaft although they cannot make the full myelination - can interact with small calibre bundles

33
Q

what transcription factor has been associated with initial Schwann cell precursors?

A

SOX10

34
Q

what happens if an injury occurs in the PNS?

A

the mature myelin cells will differentiate and start to acquire molecular features similar to the Schwann cell precursors the can proliferate and increase the progenitor pool

35
Q

how is de-differentiation different in the PNS compared to the CNS?

A

oligodendrocytes in the CNS are unable to de-differentiate

36
Q

what is SOX10?

A

classical tf that can interact with DNA and is prominently expressed by Schwann cell precursors, but is not the only tf of Schwann cells differentiation cascade

37
Q

name some of the other tfs and signals that take part in the Schwann cell differentiation cascade and their overall function:

A

laminin, NRG1, SOX2, P38, TGFβ → involved in the process of sorting and proliferation

38
Q

in regards to myelination, which portion of the process happens in the embryonic phase?

A

both neurogenesis and neural migration are almost completely confined to the embryonic phase

39
Q

when does the myelination process start / stop in humans?

A

process of myelination starts after the delivery and takes 12-13 years to complete

40
Q

when does myelination of the CNS begin?

A

myelination of the central nervous system begins during the second half of gestation in an inferior to superior, posterior to anterior pattern whereby myelination begins in the occipital lobe and continues through the temporal and frontal lobes

41
Q

what happens during the first wave of oligodendrocyte precursor cells in mice?

A

starts at embryonic day 12.5 and is generated by Nkx2.1 expressing progenitors

the majority of these oligodendrocytes disappear at day 10 of the post-natal stage

42
Q

what happens during the second wave of oligodendrocyte precursors?

A

the second wave starts from progenitors expressing the transcription factor Gsh2 (Gsx2) at embryonic day 15.5 → these cells migrate from the lateral and medial ganglionic nuclei starting from embryonic day 15.5 and spread inside the brain

part of them are present in adult life but the majority of them disappear in post-natal life

43
Q

what happens during the third wave of oligodendrocyte precursors?

A

the third wave occurs from Emx1 expressing progenitors and depends on the neuroepithelial cells in the cortex → only the last wave of the oligodendrocytes survives the embryonic phase

44
Q

describe the process of differentiation of neuroepithelial cells:

A

neural stem cell → oligodendrocyte progenitor cell → pre-oligodendrocyte → pre-myelinating oligodendrocyte → mare myelinating oligodendrogcute

45
Q

describe the final structure of oligodendrocytes wrapped around the axon:

A

oligodendrocytes roll themselves around the shaft many times (up to 40 turns) and within the spiral the cytoplasm disappears entirely - the adhesion is so intimate that the internal leaflets virtually fuse, and the extracellular membrane also disappears so the external leaflets also stick together

46
Q

what is used to measure myelin index?

A

g-ratio: the ration between the internal and the external diameter → obtained by dividing the axon diameter by the axon + myelin diameter

47
Q

what is the mean g-ratio of the nerves inside of the brain?

A

.5

48
Q

what is multiple sclerosis?

A

a chronic autoimmune mediated CNS-condied demyelinating disease characterized by a relapsing-remitting course

49
Q

when does the progressive phase begin, and what is it?

A

after 15-20 years of disease → the disease progresses without any relapse-remmission phase and there is a continuous degeneration of the nervous system

50
Q

what is MS pathologically characterized by?

A

both neurodegeneration (axonal loss and neuronal damage) and inflammation (demyelination)

presence of inflammatory demyelinating regions in the CNS → following this demyelination patients start to develop cognitive dysfunction

51
Q

what is the disorder used to model MS and how is it obtained?

A

Experimental Autoimmune Encephalomyelitis (EAE) - by injecting myelin protein in organisms something similar to MS can be induced

52
Q

what is the most famous animal model used to study MS?

A

injection of MOG in Black-6 mice → the immune dominant peptide for MOG is known (from AA35 to AA55) so its possible to synthesize several MOG and perform the immunization by using this peptide

53
Q

what can be done to treat MS in humans?

A

use immunomodulants: drugs that work on the immune system by:
- blocking the infiltration of T cells in the CNS
- blocking the exit of T cells from lymph nodes
- blocking the polarization / presentation of professional antigen-presenting cells

54
Q

what are the two tenants of an old theory describing the homeostatic interaction between oligodendrocytes and neurons?

A
  1. if the oligodendrocyte is completely detached from the axon, it cannot support the axon with the sugar and nutrients and therefore causes degeneration in the neurons
  2. in the presence of partial demyelination of the axon but in a condition in which the oligodendrocyte is still in contact with the axon, degeneration does not occur → there isn’t the electrical insulation but there is the trophic support provided by the oligodendrocytes

** demonstrated in rodents but we do not know if it is true for humans **

55
Q

describe spontaneous remyelination in MS:

A

remyelination occurs in MS although it does not result in myelin that is morphologically normal

56
Q

what is the problem with endogenous remyelination?

A

the scar → the cells providing the scar are astrocytes and because there is inflammation, a huge accumulation of inflammatory signals activates astrocytes causing the soma to increase in size