Role of Microglia in Neural Systems

Question 1

Name 4 CNS glia

Answer 1

Astrocytes
Microglia
Oligodendrocytes
NG2 cells

Question 2

What are the roles of astrocytes?

Answer 2

Induce widespread neuronal excitation - modulate CNS activity
Cause blood vessel dilation

Question 3

What is the role of oligodendrocytes?

Answer 3

Adaptive myelination - in response to neuronal activity - into adult life - required in corpus callosum for motor learning

Question 4

What are the roles of microglia?

Answer 4

Resident CNS immune cells
Regulate neuronal plasticity - by influencing neuronal activity
Synaptic pruning
Phagocytosis

Question 5

Describe the morphology of non-activated microglia

Answer 5

Small cell body

Long ramified processes

Question 6

Describe the morphology of activated microglia

Answer 6

Ameboid shape

Processes move towards lesion

Question 7

What is a microdomain?

Answer 7

Space occupied by microglial cell - forms grid-like arrangement

Question 8

How do microglia perform synaptic pruning in development?

Answer 8

Engulf axons and dendritic spines

Question 9

What is a complement protein and where are they expressed?

Answer 9

‘Eat me’ signals

On unnecessary neuronal structures - e.g. immature synapses in developing CNS

Question 10

Where are complement receptors expressed?

Answer 10

Only on microglia

Question 11

Name 2 complement proteins, the signalling pathway they activate, and the resulting action of microglia

Answer 11

C3, C1q
Activates C3-C3R pathway
Microglia phagocytose synapse

Question 12

How do microglia influence neuronal activity?

Answer 12

Processes directed to highly active neurons - by neuronally-released signalling molecules
Processes engage with soma of highly-active neurons
Decreases spontaneous and evoked firing

Question 13

Describe the process of programmed cell death. When does this occur?

Answer 13

During development
Microglia drive PCD via complement signalling
Processes attracted to relevant neuron
Project phagocytic cup - engulfs neurons

Question 14

Describe the process of synapse maturation

Answer 14

Synapse strengthened by CX3CR1-dependent mechanism - involves microglia
Synapse maturation - NMDAR subunit changes and AMPAR insertion

Question 15

What are the aberrant functions of microglia?

Answer 15

Excessive synaptic pruning - can cause cognitive dysfunction

Inflammatory cytokine release - promote neurotoxicity

Question 16

What is the effect of an early challenge to microglia in the developing CNS?

Answer 16

Primes microglia - no immediate effect on CNS

More susceptible to later challenges - delayed effect - increases later-life disease risk

Question 17

What is necessary for toxic AB effects on synapses?

Answer 17

C1q

Question 18

How has ASD been linked to microglia?

Answer 18

Deficit in microglial complement-mediated pruning - due to decreased C3 expression
CX3CR1-deficient mice have increased immature synapse density in cortex - lack of strengthening and maturation

Question 19

Which locus and type of genes have GWAS linked to SCZ?

Answer 19

MHC locus

C4 complement genes

Question 20

What are the effects of increased C4a expression?

Answer 20

Increased SCZ risk

Increased microglial activity - increased synaptic pruning

Question 21

How is synaptic density changed in SCZ patients?

Answer 21

Reduced

Question 22

Where do microglia accumulate in neuropathic pain?

Answer 22

Around terminals of damaged inputs in dorsal spinal cord - in synapse between damaged primary afferent neuron and DRG neuron

Question 23

Which molecule is released by injured sensory neurons into the dorsal horn?

Answer 23

CSF1

Question 24

What is the effect of CSF1?

Answer 24

Triggers microglial proliferation
CSF1R-expressing microglia adopt reactive phenotype - involves P2X4R upregulation
P2X4R activation stimulates BDNF release - onto neurons - activates neruonal trkB
TrkB downregulates KCC2 - causes disinhibition of nociceptive output neurons to brain