Lecture 13- The Role of Glial Cells in Brain 1

Question 1

What is a glial cell?

Answer 1

-Traditionally thought of as just the ‘glue’ holding neurons together
-Turns out glia are invovled in almost all neuronal functions
-Out number the neurons by 50 to 1

Question 2

Can you see glial cells in a Nissl stain?

Answer 2

No, not typically cause they don’t have a lot of RNA

Question 3

What are the 5 types of glial and their general functions?

Answer 3

-Schwann cells= myelination in the PNS, typically associate with 1 axon
-Oligodendrocytes= myelination in the CNS, associate with many axons
-Microglia= derived from immune cells
-Ependymal cells= line fluid filled spaces, have projections to circulate CSF/ fluid
-Astrocytes= nutrients, supporting the synapses (listen+ influence activity)

Question 4

What are the four main functions of glial cells?

Answer 4

-Synaptic modulation
-Communication
-Neuronal survival
-Brain metabolism

Question 5

What glial type is invovled in the transfer of metabolites, vessel stability and dynamic control?

Answer 5

Oligodendrocytes

Question 6

What are the main differences between neurons and glial cells?

Answer 6

-Neurons are excitable glial cells are not (glial cells traffic ions but don’t hold a net charge or fire APs)
-Neurons are primarily for communication whereas glial are for support, nutrition, glue
-Glial cells outnumber the neurons taking up 50% of the brain’s volume
-Neurons are post-mitotic whereas glial cells undergo mitosis
-Glial cells don’t have chemical synapses whereas neurons do

Question 7

Why do neurons have a fast metabolic rate?

Answer 7

Because they need to fire APs which takes a lot of energy

Question 8

What do the end feet of an astrocyte interact with?

Answer 8

Stick to blood vessel (capillary) acting at the level of blood, brain barrier

Question 9

What are the two possible locations/ types of oligodendrocyte?

Answer 9

-Typically associate with axons forming myelin sheath
-Can be in satellite location (just floating around close to neurons)

Question 10

What is the function of oligodendrocytes that are in the satellite position?

Answer 10

-Particularly more invovled in providing nutrients/ energy to the cell (not invovled in myelination which is what we typically think of as the function of oligodendrocytes)

Question 11

How is the deposition of myelin unique? What does this allow?

Answer 11

-Unique specialization of vertebrates
-This is a key driver of evolution as myelin speeds up conduction velocity allowing us to grow to be bigger as jumping from node to node means the distance travelled becomes less. Note: the more distance travelled by an AP the more energy lost (don’t want this)

Question 12

What are the four evolutionary advantages the myelination provides?

Answer 12

1. Myelination strongly reduces energy consumption. Action potentials and ion currents are restricted to less than 0.5% of the axon’s surface.
2. Rapid impulse propagation/ increased conduction velocity allowed complex yet compact higher nervous systems to evolve.
3. Muscle control became the basis for the development of complex predatory and escape behaviour, which ultimately drove body size and vertebrate evolution
4. Neurotrophic contribution required for the long-term integrity and
   survival of axon

Question 13

What is the term for the myelin sheath either side of the node of ranvier?

Answer 13

Portions covered with myelin are the internodes (this is the section the APs skip as there are no ion channels)

Question 14

What organelle is there lots of at the node of Ranvier?

Answer 14

Lots of mitochondria as it energy extensive to fire APs

Question 15

What is the difference between myelination in the PNS versus the CNS?

Answer 15

-PNS is done by Schwann cells and they only associate with 1 axon/ axonal segment
-In CNS is done by oligodendrocytes which associate/ wraps one part of axon on multiple axons

Question 16

What is the difference in unmyelinated axons in the CNS and PNS? In what cases would you have unmyelinated axons?

Answer 16

-In the CNS axons just remain naked. This would occur when the the axons are short range as in this case there is no advantage to myelination (signal is pretty fast anyway)
-In the PNS Schwann cells associate/ surround

Question 17

In what matter are oligodendrocytes found?

Answer 17

White matter= lipid like myelin gives it it’s white appearance

Question 18

What is myelin basic protein?

Answer 18

-Basic as has a pH of 10
-Responsible for holding layers of myelin together

Question 19

What is the parts of the myelin wrap called in the CNS and then also the PNS?

Answer 19

-For Oligodendrocyte wrapping there is an inner and outer tongue
-For Schwann cells the terminology is instead an inner mesaxon and outer mesaxon (associates with the cytoplasm)

Question 20

What is a g-ratio? What is ideal?

Answer 20

Thickness of myelin proportional to axon diameter
g ratio = d/D = 0.6 - 0.7 (ideal)

Question 21

How does axon wrapping occur? What is the process?

Answer 21

-Start with oligodendrocyte precursor cell
-This then starts to grow processes which associate with neighbouring axons (selection of section)
-Contact stabilization and polarization
-Lateral and radial expansion of the wrap due to membrane trafficking where phospholipids are trafficked to the feet
-Channel clustering also helps in working where the nodes should be between the wrapped sections
-Then myelin basic protein mRNA trafficking occurs and translation to result in the compaction of the sheath. At this point incisures/ clefts also appear
-Finally have compact myelin and a mature oligodendrocyte (not making any more proteins, absence of mRNA), incisures close

Question 22

How does local protein synthesis occur in oligodendrocytes?

Answer 22

-Synthesis of myelin proteins occur distal to the cell’s body
-Transport of RNA granules containing mRNA and ribosomes occurs via microtubules
-These exist/ travel from the nucleus of the oligodendrocyte all the way around the myelin and sheath in the paranodes (between nodes)

Question 23

What is the IPL versus the MDL?

Answer 23

These are the two areas of contact myelin

-IPL= intraperiod: 2 outer layers of plasma membrane and ECS
-MPL= major dense: 2 inner layers of plasma membrane cytoplasm

Question 24

What are the different proteins that exist in the myelin for the PNS as opposed to the CNS?

Answer 24

-P0 protein zero (PNS)
-MBP myelin basic protein (PNS/CNS)
-PMP 22 peripheral myelin protein (22kD) (PNS)

Question 25

What are the differ regions in relation to the node and internode areas? What is the function of each area?

Answer 25

Node which contains a lot of sodium channels
PN – paranodal. Major function is anchoring to axon.
JP – juxtaparanodal. Have potassium channels where potassium can flowing out.
IN – internode. Wrap.

Exist in this order

Question 26

Why are the location of the internodes stable? Why is this important?

Answer 26

-Internodes are stable due to specific proteins anchoring the wrap to the axon :
Neurofascin= glial/ axon cell adhesion molecule
Contactin= glial/ axon cell adhesion molecule (again!)
Caspr= transmembrane protein on axon. Contactin-associated protein.

Also the PN (paranoidal junction) region works to seal the periaxonal space to the outside

-It’s important that internodes stay in the same place because if you think about it if the wrap shifted then the channels in the node would be covered and you wouldn’t be able to get depolarization/ APs

Question 27

What percentage of the axon is covered in myelin?

Answer 27

99%

Question 28

How does myelination effect the frequency at which an axon fires and how does this in turn impact on function?

Answer 28

-Nodally sourced energy is used for basal activity or small-diameter myelinated axons with short internodes: fire at low frequencies.

• Large myelinated axons firing high frequency

Question 29

What are MCTs (monocarboxylate transporters )?

Answer 29

-Extracellular membrane channels
-Transport lactate, pyruvate, and ketone bodies
There are 14 or more MCTs
-MCT1, 2, 4 are the major types in CNS
-Evidence in oligodendrocytes

Question 30

How do oligodendrocytes ‘feed’ neurons?

Answer 30

-Oligodendrocytes uniquely provide metabolic support to neurons/axons

This occurs via:
-MCT1- oligodendrocyte plasma membrane
MCT 2 - axon plasma membrane under Myelin

-These carry molecules with one carboxylate group (monocarboxylates), e.g. lactate and pyruvate, across biological membranes. Essentially this means the oligodendrocytes are providing the neurons with energy.

Question 31

How does the Oligo/Schwann cell know the axon needs energy?

Answer 31

The metabolic supportive function of oligodendrocytes is regulated
by glutamate (Major excitatory neurotransmitter) binding to the NMDA receptor

Question 32

How are MDMA receptors composed in terms of their subunits?

Answer 32

-Its a tetramer meaning is composed of four subunits
-Different subunits have different affinities
-They also have a ligand binding domain and a trans-membrane domain

Question 33

What is the effect of excessive NMDA receptor signaling?

Answer 33

-Excitotoxicity
-Confirmed to be closely related with demyelinating white matter diseases, such as cerebral palsy, multiple sclerosis, schizophrenia, and
Alzheimer’s disease

Question 34

What is the most famous disease associated with myelin?

Answer 34

-Multiple sclerosis refers to scars (sclerae- known as plaques or lesions) particularly in the white matter of the brain and spinal cord

-Classed as an autoimmune disease as the oligodendrocytes are targeted by microglia meaning that myelin sheath disintegrates