Glia: Microglia and astrocytes Flashcards

1
Q

What are the different types of glia?

A

Non-myelinating glia:
Astrocytes - star-shaped = nutrition + support function.
Microglia = derived from the mesoderm + defensive function.

Myelinating glia:
Oligodendrocytes = form myelin around neurones in CNS. = CNS myelination
Schwann cells = warp around peripheral nerves to form myelin. = PNS myelination.

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2
Q

What are neural cells?

A

Neural cells refer to cells derived from the neural tube = neurones and most glia.
(Microglia are neural cells with non-neural origin).

Divided into Microglia and Macroglia.
Macroglia include:
Schwann cells (PNS myelination)
Oligodendrocytes (CNS myelination)
Astrocytes = nutrition + support.
Radial glia = migration scaffolds

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3
Q

What are the myelinating glia?

A

Oligodendrocytes = CNS myelin.
Schwann cells = PNS myelin.

Insulating + increase speed of conduction of AP, protection of axon and support role.

Remember the nodes of ranvier + saltatory conduction.

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4
Q

What is the role of Radial Glia?

What happens to Radial Glia after development?

A

Embryonic scaffold throughout the CNS for migration.
Adhesion molecules and matrix assist migration in developing NS.

Radial glia cells persist after development, in the cerebellum = Bergmann glia…. in the retina = Muller cells.

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5
Q

What are Ependymal cells?

A

Glia
Line ventricles in the brain, with beating cilia.
Maintain flow of CSF through ventricles and central canal of brain.

Specialised ependymal cells participate in secretion of CSF.

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6
Q

What is the embryonic origin of glia?

A

From neural tube = neurones, astrocytes, oligodendrocytes.
From Neural Crest = Schwann cells.
Microglia derived from macrophages before BBB forms, but are still classed as neural cells but with non-neural origin.

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7
Q

What is the process of gliogenesis?

A

Neuroepithelial stem cells (NSC) give rise to neurones and glia.
Glial-restricted precursors can divide into Astrocyte precursors or O2A progenitors.
Astrocyte precursors divide into Type 1 astrocytes.
O2A progenitors divide into Type 2 astrocytes or oligodendrocytes.

Gliogenesis does not occur for Schwann cells or Microglia!!!

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8
Q

Which of the main Glia are found in the CNS?

A

Astrocytes, oligodendrocytes, microglia, Ependymal cells, Radial glia.

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9
Q

How are astrocytes different in shape from microglia?

A

Astrocytes with large cell bodies, and large, robust projections.
Astrocyte function depends on location in CNS…

Microglia cell bodies are smaller, with finer, more branched projections.
Exist in different states - active/inactive, with changes to conformation.

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10
Q

What is the dual origin of microglia?

A

Non-neural origin.
Originate from yolk sac (associated with placenta)… but is lost after birth.

Yolk sac contains Hemangloblast cells = primitive macrophage and erythrocyte source.
Primitive macrophages then migrate to CNS (before BBB forms) where they mature into microglia in the CNS.

But also evidence that microglia come from monocytes in the blood that directly invade the brain.

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11
Q

What is the evidence to suggest the monocyte origin of microglia in addition to the yolk sac source?

A

Monocytes enter the developing CNS and change in morphology as monocytes transform into microglia.

Bone marrow chimeras show brain becoming populated by DS cells of haemopoetic origin.

However, microglia share many cell surface receptors and antigens which are exclusive to macrophages. But immunocytochemical studies of transplanted CNS tissue show it becomes populated by microglia bearing markers for myelomonoctic cells.

= majority from yolk sac, but some comes from monocytes generated in the bone marrow.

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12
Q

What are the different types of microglia?

A

Ameboid = DEVELOPMENT = round, develop in clusters, proliferative and migratory = concentrated in the corpus collossum.

Ramified = adult form in brain = with small cell bodies, fine, branched projections…

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13
Q

What are the different states of microglia?

A

Ramified microglia can be identified by structure and antigens expressed on surface.

Resting state = finer processes with OX-42.

Activated state = Thick processes, with vimentin + Migratory + proliferative.

Phagocytic = globular, proliferative…. with vimentin, OX-42 and OX-8!

All states express OX-42…

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14
Q

What are the functions of microglia?

A

Resting cells provide support and protect neurones and release growth factors.

Viral/microbe antigens causes activation and microglia migrate towards source of antigen.

Macrophagic like response with RONS, pro-inflammatory cytokines like TNF-alpha.
+ PROLIFERATVE!

Destroy degraded/damaged neurones = myelin fragments cause activation of microglia, causing conversion to phagocytic state.
= to consume neurone, debris etc..

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15
Q

What do microglia respond to?

A

respond to viral/microbe antigens/beta amyloid+ ischaemia + cytokines from damaged neurones.

BUT also respond to activated astrocytes which release pro-inflammatory cytokines too.

Microglia are activated by beta-amyloid (Alzheimer’s) = causing microglia to kill neurones by production of RONS.

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16
Q

What is the role of microglia in neurodegenerative disease?

A

Microglia are activated by beta-amyloid (Alzheimer’s) = causing microglia to kill neurones by production of RONS.

However microglia do not kill healthy cells .

This is the point of contention - some think microglia are only activated to dead cells to remove debris, while others think they actively kill neurodegenerated neurones.

Or that microglia are being protective or failing due to disease state?

17
Q

What are the two classes of astrocytes?

A

Protoplasmic astrocytes = associated with cell bodies/gray matter.

Fibrous astrocytes = associated with axons/white matter.

18
Q

What are the general roles of Protoplasmic and Fibrous astrocytes?

A

Protoplasmic astrocytes associated with cell bodies are vital for transporting K+ and glucose, maintaining optimal interstitial environment for neurones and maintaining the BBB.

Fibrous astrocytes are associated with axons in white matter = support and provide structure for axons and form scar tissue.

19
Q

What are two processes of astrocytes?

A

Astrocytes can be stained by GFAP, an intermediate filament.

Perivascular feet - make contact with blood vessels = glucose, O2, K+/Na+/Ca2+ uptake etc.

20
Q

What are the functions of astrocytes?

A

Determinant of extracellular volume.

Expression of channels and receptors = maintain interstitial environment and glucose, K+ , NT (particularly glutamate), Ca2+ signalling.

Maintenance of BBB

Growth and death of neurones.

Structural support.

Axonal guidance in development = provides pathways used by neurones to migrate to target tissue. E.G =Rostral migratory stream = SVZ cells migrate to the olfactory bulb along astrocytic networks, without radial glial cells.

21
Q

How do astrocytes function in axonal guidance?

A

Provide pathways used by neurones to migrate to target tissue. E.G =Rostral migratory stream = SVZ cells migrate to the olfactory bulb along astrocytic networks, without radial glial cells.

Axonal guidance cues like CAMs, cadherins, integrins which interact with neurones.
e.g. NCAMS on neurone interact with phosphocan on astrocyte surface

22
Q

Which cells are most numerous in the CNS?

A

Astrocytes = more than 50 times the number of neurones.

23
Q

How do astrocytes provide a supporting role?

A

Simply giving structure by wrapping around area of synapse and protection of synapses.

24
Q

What is the role of astrocytes in neuronal growth/death?

A

Release Growth factors GDGF’s.
Cytokines (anti-inflammatory)

In axonal damage, astrocytes proliferate around site of damage and can aid repair or prevent neuronal degeneration! by forming glial scars preventing axon from regenerating.

25
Q

How do astrocytes work in calcium signalling?

A

There are gap junctions between astrocytes that allow communication rapidly via calcium signalling.

Calcium waves have been observed in culture, where calcium sweeps between astrocytes very quickly.
= through interconnected neurones.

= thought to synchronize neuronal behaviour.
= Provide information from different synapses, maybe from active synapses…

During a calcium wave = synaptic cleft Ca2+ decreases - further inhibiting NT release, despite arrival of AP’s…
After calcium wave terminates = Synaptic cleft Ca2+ levels return to normal.

26
Q

What is special about calcium waves?

A

Simulatenously synchronise all the synapses an astrocyte has enveloped - this calcium wave could coordinate synapse into synchronously firing groups = all the synapses within an astrocytes domain of synaptic influence.

Through strictly astrocytic pathways - 1 group of neurones could influence a distant group of neurones - influencing huge parts of cognitive functioning.

27
Q

How are astrocytes implicated in glutamate?

A

Astrocytes clear released glutamate from synaptic cleft using GLAST and GLT-1 transporters.
The glutamine synthase converts to glutamine, where it can be shuttled back into neurone via glutamine-glutamate shuttle.

Very important for controlling glutamate concentration in the synapse to prevent excitotoxic death.

28
Q

How does astrocyte influence BBB?

A

Formation of BBB = to exclude circulating immune effectors from entering brain, such as Ig’s and complement.

MHC antigens are not expressed in the brain.
Minimal neutrophil recruitment after excitotoxin-mediated neuronal degeneration.
Naive T cells cannot cross BBB!

The BBB gives the brain immunological privilege.

29
Q

What is immunological privilege?

A

The brain does not express MHC..

Allografts in the rest of the body would be rejected, except if placed in the CNS = no rejection.

Oligodendrocytes transplanted into the CNS of some mice are not rejected.

= Opens the possibility of tissue transplantation in neurodegenerative disease!

30
Q

How is BBB formed?

A

Astrocyte feet and peicytes surround the endothelium of the blood vessel
= Physically prevent the invasion of cells and limit transportation of material into brain.

31
Q

What is the main energy source of the brain?

How is it transported?

A

Glucose - transported across BBB by astrocytes.

BUT…. there is the astrocyte-neurone lactate shuttle = during neural activity, glia use anaerobic glycolysis to meet energy needs and produce lactate…

Neurones then use this lactate to fuel metabolism.

With GLUT145K transporters in astrocytes and then GLUT1 55K in endothelial cells.

GLUT5 in microglia.

Neurones uptake glucose via GLUT3

32
Q

What are the functions of channels and receptors in astrocytes?

A

Express NT receptors and ion channels usually used by neurones…
Such as 5HT receptors, astrocytes in vicinity of serotonergic synapses…
= coordinate activity of astrocytes with neurones.

Control of clearacnce of ions from interstitium = maintain appropriate ion balance..

33
Q

How do astrocytes control extracellular volume?

A

Astrocytes can modulate their size and therefore influence the excitability of neurones…

By swelling or shrinking (as a result of glutamate/adenosine stimulation)… can determine the volume fraction of extracellular space around a synapse.

= Altering the effective concentration of NTs in the synapse.
= regulate excitability.

34
Q

How do cytokines influence the CNS?

A

Cytokines are produced by both microglia and astrocytes, as well as neurones.

Microglia recruitment in damaged axons/neurones….

Can alter cell survival and proliferation.

IFN-y, IL, TNF-a, TGF etc.

35
Q

What cytokine receptors are expressed?

A

Microglia, astrocytes and oligodendrocytes can express receptors for many cytokines….

gp130 and CNTR = bind IFN-y, IL-6..
IL-1, IL-4, TGF-B etc..

Microglia express IL-6…

36
Q

What signalling pathways are associated with cytokines?

A

JAK/Stat pathway associated with IL-4 and IFN-y.
Stat proteins dimerise due to phosphorylation by JAK kinases on IFN-y receptor.
STAT dimerisation and full activation by phosphorylation leads to nuclear translocation and affects gene transcription.