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LSM3216 Neuron Dev and Diseases > Lecture 8 - Glia Biology I > Flashcards

Lecture 8 - Glia Biology I Flashcards

1
Q

Glial cells

What are these cells?
Where are they found?
What do they do?

A

What are these cells?
o Macroglial: astrocytes, oligodendrocytes/ Schwann cells
o Microglial

Where are they found?
o CNS/PNS

What do they do?
o Myelination, BBB, BSCB, inflammatory response

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2
Q

What is the glia-neuron ratio?

A

About 1:1 depending on the area of the brain
(outdated ratio is 10:1)

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3
Q

What is the Major Classification of Glial cells

A

Macroglial
- Astrocytes (most abundant)
- - Star shaped. Largest glial type
- Oligodendroglial (CNS)/ Schwann cells (PNS)
- - forms myelin sheaths around axons fewer cell processes.
- NG2
- - (OPC, polydendrocytes)

Microglial
Smallest cell bodies among neuroglia

Others
“glial like” in CNS: Ependymal cells line most ventricular system of CNS.
Choroidal cells forming inner layer of the choroid plexus. Secrete CSF

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4
Q

What do glial cells do?

A
  1. Support neurons, providing structure. Insulate neuronal groups and synaptic connections.
  2. Housekeeping - promote efficient signaling between neuron/take up chemical transmitters released by neuron.
  3. BBB/B-Choroid barrier.
  4. Myelination.
  5. Source growth factors/cytokines (GDNF, interleukins etc).
  6. Injury response/scavange - remove debris.
  7. Neurodevelopment — “radial glial’ guide migrating neurons and in directing outgrowth of axons.
  8. Controlling intracerebral blood flow.
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5
Q

How are cell types classified?

A

Based on
Morphology (what it looks like — shape and sizes)
Location (where they are found)
Molecular contents (surface/intracellular markers — immuno/ molecular)
Cellular properties (biochemical or electrophysiological attributes)
Functions (what they do and can do)

Challenge: Cells can change any of these with time and situation

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6
Q

How are astrocytes classified based on morphology?

A

Astrocytes —’star-shaped’ process-bearing cells in the CNS

2 main types based on morphology
*Protoplasmic (predominantly in gray matter)
*Fibrous astrocytes (predominantly in white matter)

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7
Q

What is GFAP?

A

Glial fibrillary acidic protein (GFAP)- an intermediate filament (IF) marker for some astrocytes

IF of astrocytes:
GFAP/Vimentin/Nestin/Synemin
Multiple markers to define a specific population

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8
Q

What are the features of Astrocytes exocytosis?

A

Astroglial exocytosis is slow

Express proteins characteristic for neuronal synaptic vesicles (VAMP2)/proteins found in exocytotic trafficking vesicles of non-neuronal cells

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9
Q

Where does the blood brain barrier (BBB) reside?
What is it made of?

A

BBB: resides anatomically in the endothelium of capillaries

“Neurovascular unit” —(dynamic system affecting blood flow in brain)
o Vascular cells (pericytes, vascular smooth muscle cells (VSMCs), endothelial cells)
o Glial cells (astrocytes, microglia, oligodendrocytes)
o Neurons

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10
Q

what are the 6 major functions of the Blood Brain/Spinal Cord Barrier (BBB/BSCB)?

A

Permeability- barrier depends on special property of the capillary endothelium. Other capillaries are fenestrated, CNS endothelial cells have tight junctions and highly resistant to passage of ions or small molecules

6 major functions

  1. Large molecules (plasma protein) excluded from CSF
  2. Ionic composition & glucose concentration of extracellular fluid in CNS are highly controlled — don’t fluctuate much.
  3. Brain-spinal cord protected from effects of neurotransmitters etc. in the blood (e.g., epinephrine from adrenal gland).
  4. Neurotransmitters made in CNS do not leak into general circulation.
  5. Toxic material excluded because of size or solubility.
  6. Astrocytes can influence local blood flow and not just a passive barrier.
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11
Q

How do Brain capillaries have selective permeability?

A

Some areas of brain do not have a good BBB
Neurosecretory products pass across into circulation like pituitary hormones (TRH, GRH etc).

Most substances that must cross BBB are NOT lipid soluble by using specific carrier-mediated transport system. E..g, Glut1 (glucose transporter isotype 1).

BBB can be damaged by viral infections and some neurological diseases

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12
Q

What is Cerebrospinal fluid (CSF)?

A

Brain ventricles contain fluid produced within the brain and is continuous with the spinal cord

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13
Q

What is the blood-CSF barrier (BCSFB)

What is the function of CSF?

A

Another fluid barrier: Blood-CSF barrier (BCSFB) exist in the choroid plexus & the arachnoid mater

BBB & BCSFB are not only anatomical barriers, but also dynamic tissues that express multiple transporters, receptors and enzymes.

CSF communicates with brain interstitial fluid and maintain constant environment
*Flow in ventricle — one way.
*Cushion the brain mechanical
*Serve as lymphatic system for brain

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14
Q

What is the Choroid plexus (CP), and what are its features?

A

a network of blood vessels in each ventricle of the brain, producing the cerebrospinal fluid.

  • The tight junctions of CP are different from BBB.
  • CP capillaries are more fenestrated and more permeable.
  • Endothelial cells have tight-junctions so that substances cannot pass between cells into the CSF in the ventricles but transported.
  • Cells here have active transport mechanisms for ions, glucose and amino acids but large molecules are unable to pass.
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15
Q

How does entry into CSF occur?

A

*Diffusion of lipid-soluble substances.
*Facilitative and energy-dependent receptor-mediated transport of specific water-soluble substances.
*Ion channels

Production of CSF- Active secretion of CSF not just filtration of plasma.
CSF and extracellular fluids of brain are in steady state.

*Composition of CSF may be altered in disease.
*Normal CSF has no RBC. Tumor or infection, disturb distribution into CSF.
*Protein contents in CSF is lower than in plasma.

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16
Q

Hydrocephalus (“water in the brain”)- increase in volume of CSF in ventricles.

What are the possible causes?

A

Increase in intracranial pressure can be harmful to brain.
3 possible causes:
1. Oversecretion of CSF
2. Impaired absorption of CSF
3. Obstruction of CSF pathway.

17
Q

crossing the BBB is a Significant challenge - how can it be achieved?

A
  • Prodrug strateqies: enhance the lipophilicity or to target specific transport systems.
    e.g., dopamine — do not cross BBB due to its hydrophilic structure. Convert to its a-amino acid, L-Dopa, enables the brain to uptake 1 via the large aminoacid transporter of type 1, (LAT 1).
  • Pharmaceutical approach: develop new vehicle for transport of drugs.
    Use of liposomes: transferrin surface-conjugated liposomes includes the delivery of the anticancer drug 5-fluorouracil (5-FU) for glioma treatment.

*Nanoparticles

*Physical methods: hyperthermia, ultrasound etc

18
Q

How are neurons myelinated in the CNS and PNS?

A

Not all neurons are myelinated
Made by oligodendrocytes in CNS — 1 oligodendrocyte can myelinate many axons (CNS lack of space).
Schwann cells in PNS — generally 1 schwann per axon.

Myelination allows rapid transmission along axon

19
Q

What is the Organization of the Node of Ranvier?

A

Juxtaparanode
Paranode
Node of Ranvier

20
Q

Myelination
Historically, myelin: a good material for structural studies — X-ray, EM, neutron diffraction. Why?

A

Reason:
* Highly ordered and regularly repeating structure.
* Abundant, exceptionally low buoyant density making it easy to purify

  • Recent focus of studies: to assemble a model of how myelination comes about by interactions of various proteins.
  • Identifying genes involves in building myelin is the current challenge
  • How to remyelinate for repairing damaged neuron
21
Q

Myelination — a developmentally regulated process
Wht are the steps of myelination?

A
  1. Specific association of schwann cells with axon.
  2. Wrapping of myelin (rapid membrane biosynthesis)
  3. After 1st turn- this sheet of membrane must insinuate itself under the first wrap of the sheath.
  4. Spiral growth of mylein sheath proceeds through displacement of the previously deposited mylein layer, in direct association with the axonal surface.
  5. Repeated wrapping through continuous insinuation of the growing inner layer of membrane about the axon, rather than through migration of Schwann cell body about the axon.
22
Q

What are some myelin Proteins that cause mutations/diseases?

A

Injection of Myelin basic protein (Mbp) causes experimental autoimmune encephalomyleitis (EAE) — T-cell invasion of CNS and PNS & demyleination with chronic relapsing paralysis.
Model for multiple sclerosis (MS).
Other myelin components also cause encephalomyleltis
-Proteolipid protein (Plp1), myelin-associated glycoprotein (Mag), myelin oligodendrocyte glycoprotein (Mog), astroglial S-100 ß protein

23
Q

how does microglia act as a “brain macrophage”?

A

Antibody specific to antigen on surface of microglia
Normal — small, ramified structures (unlike peripheral macrophage)

“Activation” of microglial (human brain).
Shift in cell morphology from one type to another.

24
Q

How can “side reactions” of microglia activation be detrimental to neuronal health?

A

Microglia & astrocytes: active players in pro-inflammatory and anti-inflammatory activities

25
Q

Why is CNS repair not usual?

A

Astrogliosis — neurotrama induced reactive astrocytes

Anisomorphic reactive glia
- Glia cells at the site of injury
- Happens in weeks/months

Isomorphic reactive glia
- Glia cells far away from the site of injury

Both astrocytes & microglia are activated

26
Q

What is the Response to any CNS pathologies?

What happens with the IFs in gliosis?

A

(neurotrama, stroke, neurodegenerative diseases, tumor) — IFS increased in expression.
Reactive astrocytes — gliosis — immediate response -5 glial scar (tightly compacted limited glial margin).

Reactive astrocytes responses (mutant mice)
o (GFAP-/-) or vimentin (Vim-/-): reduced IF.
o Astrocytes from (GFAP-/- Vim-/-): completely devoid of IF

In reactive astrocytes from WT: increase in the IFS (GFAP, vimentin, and nestin).

However, In reactive astrocytes from GFAP—/—: IFS contain vimentin and nestin.
o Vim—/— mice contain GFAP only, since nestin can neither self-assemble nor co-assemble with GFAP. Thus, nestin needs Vimentin for assembly.

27
Q

Gliosis — hypothesis: astrocytes implicated as
inhibitors of neuroregeneration
How do we know?

A

Hall marks of reactive gliosis — hypertrophy of astrocytic processes/upregulation of IFS
In GFAP-/-Vim-/-:
o Limited hypertrophy of cell processes.
o Synaptic regeneration observed.
Perhaps, reactive astrocytes as potent inhibitor of neuroregeneration

o Reactive astrocytes may exacerbate tissue damage — releasing inflammatory cytokines (TNF-a) which inhibit neurite outgrowth and kill oligodendrocytes, produce/release arachidonic metabolites, NO, reactive oxygen species — affecting cell survival.
(Not as much as microglial).

28
Q

What is important as a result of gliosis?

A

Importance of:
Reactive astrocytes -restricting inflammatory response to damage, thereby protecting healthy CNS tissue.
Glial scar - preserving tissue integrity/mitigating
further inflammatory damage

29
Q

What occurs at the site of CNS injury?

A

o Distal ends of the severed axons form dystrophic growth cones when exposed to the damaged glial environment.
o Early phase of injury: myelin associated inhibitors from intact oligodendrocytes and myelin debris restrict axon regrowth.
o Recruitment of inflammatory cells and reactive astrocytes results in glial scaring and fluid filled ‘rubbery’ cyst (contains chondroitin sulphate proteoglycans).
o CSPG further limit regeneration.

Overall result — not favorable axon repair.

30
Q

What is it about scar that impedes neuronal migration?

A

‘Rubbery’-like substances forming a impervious membrane to neuronal migration

Scar - high amounts of ECM proteoglycans sulphated GLYCOSAMINOGLYCAN (GAG).
o Astrocytes produce 4 major classes of proteoglycan
- Heparan sulphate proteoglycan (HSPG)
- Dermatan sulphate proteoglycan (DSPG)
- Keratan sulphate proteoglycan (KSPG)
- Chondroitin sulphate proteoglycan (CSPG)

o CSPGs form a relatively large family (includes aggrecan, brevican, neurocan, NG2, phosphacan (sometimes classed as a KSPG) & versican)
o Expression of these CSPGs increases in the glial scar in the brain and spinal cord
of mature animals.
o Other CNS myelin associated proteins are released on damage acting as inhibitors.

LSM3216 Neuron Dev and Diseases (10 decks)

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