Microglia

Question 1

Describe the basic morphological features of microglial cells and their relationship to other cells in the brain:

Answer 1

Morphology:

• smallest glial cells in the CNS and highly dynamic
• resting (or surveillant) microglia characterised by a small soma and extensively branched processes
• upon activation, they transition into an amoeboid form, characterised by a large, rounded soma and retracted processes, enabling motility and phagocytic activity

Structural adaptations:

• membrane is enriched with pattern recognition receptors to sense damage-associated + pathogen-associated molecular patterns
• highly motile processes

Relationships:

• work synergistically with astrocytes in maintaining the CNS microenvironment
• interact with endothelial cells at the BBB to support vascular integrity
• communicate with neurones via direct contact regulating synaptic activity by pruning

Question 2

Relate the morphology of microglial cells to their specialised functions:

Answer 2

Resting state:

• branched morphology allows efficient surveillance over a wide area
• processes dynamically extend and retract to monitor and respond to local stimuli, including synaptic activity
• low expression of inflammatory markers prevents unnecessary immune activation

Activated state:

• Amoeboid morphology supports migration and phagocytosis
• up-regulation of surface markers like MHC class II, CD68, and CD11b facilitates antigen presentation and phagocytic functions
• Secretion of inflammatory mediators promotes clearance of pathogens and debris while recruiting peripheral immune cells

Morphology and activation are not binary; microglia exhibit transitional forms tailored to specific tasks, such as tissue repair or neuroprotection

Question 3

Discuss the embryonic origin of microglia and growth potential in injury and disease:

Answer 3

Origin:

• derived from yolk sac progenitor cells during early embryogenesis
• migrate to the developing CNS before the formation of the blood-brain barrier (BBB)

Growth potential:

• in repose to disease microglia;
• Rapidly proliferate at the site of damage
• Release pro- and anti-inflammatory factors to modulate repair and
  clearance
• Switch to a phenotype that supports tissue remodeling

Question 4

What are the central homeostatic functions of microglial cells in the CNS ?

Answer 4

Continuous surveillance:
- processes scan the CNS microenvironment for damage, pathogens, and altered neuronal activity
- microglia adapt responses based on detected signals

Synaptic maintenance:
- prune excessive or underused synapses during development (via complement signalling pathways, C1q, C3)
- modulate synaptic plasticity in adulthood by secreting BDNF or removing dysfunctional synapses

Regulation of Neurotransmitter Levels:
- prevent excitotoxicity by modulating extracellular glutamate
- interact with astrocytes in glutamate recycling

Support of Neuronal Health:
- Release neurotrophic factors (e.g., IGF-1, BDNF) to promote neuronal survival.
- Protect neurones under mild stress by scavenging extracellular debris

Question 5

What are the immune functions of microglia ?

Answer 5

Act as resident macrophages of the CNS, bridging innate and adaptive immunity

Phagocytosis - detect and engulf apoptotic cells, pathogens, and myelin debris using receptors

Cytokine production:
- pro-inflammatory cytokines activate peripheral immune responses
- anti-inflammatory cytokines resolve inflammation and support repair

Upregulation of MHC class II enables microglia to present antigens to T cells, facilitating adaptive immune responses

Question 6

Define efferocytosis and describe the central role of microglia in this essential role:

Answer 6

Efferocytosis is the process of recognizing, engulfing, and degrading apoptotic cells without inducing inflammation

Microglial role:

• specialised receptors (e.g., TREM2, MerTK, and phosphatidylserine receptors) detect “eat-me” signals on apoptotic cells
• efficient efferocytosis prevents secondary necrosis and the release of pro-inflammatory substances
• enhances tissue repair by clearing debris and secreting pro-resolving mediators

Question 7

Describe the roles of microglial cells in neuroplasticity during development and in adulthood:

Answer 7

Developmental role:

• sculpt neural circuits by synaptic pruning, removing weak or redundant synapses
• guide axonal growth and neural connectivity through trophic factors

Role in Adulthood:

• support long-term potentiation (LTP) and synaptic remodeling essential for learning and memory
• respond to increased neural activity by strengthening synapses or clearing damaged ones

Question 8

Identify the importance of microglia to maintenance of the blood-brain barrier

Answer 8

Regulation of BBB Integrity:

• microglia interact with endothelial cells and pericytes to strengthen the tight junctions of the BBB
• secrete factors like TGF-β and VEGF to promote BBB stability

Response to Disruption:

• upon BBB damage, microglia migrate to the site, clearing infiltrating pathogens and debris
• Release vascular repair factors to restore BBB integrity

Continuously monitor the periphery for pathogen infiltration and contribute to limiting inflammatory spread into the CNS