Glial Cell Biology ILO 5 - Identify key signalling molecules released by brain glial cells and their downstream targets

Question 1

What protein shows increase expression on the end-feet of astrocytes interacting with blood vessels? What is its role?

Answer 1

Aquaporin 4 - Aqp4
Water channel that can also uptake K+
Densely expressed on the end-feet of astrocytes interacting with blood vessels
Plays a role in fluid homeostasis

Question 2

What transporters are present on astrocytes that play a role in maintaining a healthy pH?

Answer 2

MCT1/4 - monocarboxylate/proton cotransporter, specific to astrocytes
NBCe1 - Bicarbonate cotransporter, ATPase
NHE1 - proton/Na+ transporter, H+ out, Na+ in
Proton pump

Question 3

What neurotransmitters are astrocytes able to uptake?

Answer 3

Glutamate, GABA, glycine and serotonin

Question 4

Briefly explain astrocyte glutamate recycling

Answer 4

Glutamate uptake through glutamate transporter (GLT1) out of synaptic space
Converted into precursor glutamine by glutamine synthase
Glutamine release by astrocyte and taken up by presynaptic neuron
Metabolised into glutamate by phosphate activated glutaminase (PAG)

Question 5

What molecules can astrocytes release?

Answer 5

Glutamate, purines (ATP), GABA, D-serine
Growth factors (BDNF)
Cytokines (TNFa)

Question 6

Describe the handling of glucose by astrocytes

Answer 6

Uptake glucose from the blood, ‘feed’ metabolites to neurons
Only cells in the brain able to store glucose as glycogen
Break down glycogen in normal activity such as neuronal activation and during pathophysiology such as ischaemia

Question 7

Briefly describe the astrocyte-neuron lactate shuttle

Answer 7

Glucose is taken up from the blood through GLUT transporters and stored as glycogen
Lactate is produce from the conversion of pyruvate by lactate dehydrogenase (LDH5)
Glutamate release stimulates glycogen activation
Neurons express MCT2 and import lactate
Lactate metabolised by LDH1 to pyruvate which enters Krebs cycle to produce ATP

Question 8

How is lactate released by astrocytes believed to act like a signalling molecule?

Answer 8

Lactate released by astrocytes believed to act directly on some neurons via receptors e.g. noradrenergic neurons
Can increase firing rate and neurotransmitter release

Question 9

What is the fractalkine (CX3CR1/CX3CL1) signalling axis and how does it contribute to microglia activation?

Answer 9

Fractalkine ligand (CX3CL1) released by neurons
Fractalkine receptor (CX3CR1) found on microglia
Interaction is an ‘off’ signal - keeps microglia in a healthy, non-activated state
In chronic inflammation, no ‘off’ signal and no inhibition of microglia

Question 10

What are the two isoforms of the fractalkine ligand?

Answer 10

Membrane bound GPCR

Soluble receptor - becomes active when cleaved by metalloproteases located in perineuronal networks

Question 11

What other cells express fractalkine receptors and when might they be present in the brain?

Answer 11

Monocytes, dendritic cells, NK cells

Only enter the brain during extreme neuroinflammation

Question 12

What is CD200 and what does it do in relation to microglia?

Answer 12

Glycorprotein whos expression is restricted to neurons and its receptor restricted to microglia
Acts as an ‘off’ signal