Lecture 9 - The role of Glial Cells in the Brain I

What is the developmental lineage of microglia?

Microglia arise from a myeloid lineage, derived from hematopoietic cells of the yolk sac/bone marrow, unlike other CNS glial cells that are ectodermal

What proportion of glial cells do microglia make up, and what do they look like?

They account for ~5–20% of glial cells, are small and highly branched, sometimes resembling astrocytes, but are difficult to identify morphologically

What is the primary role of microglia in the CNS?

They act as the brain’s resident immune cells, performing surveillance, immune defense, and maintaining homeostasis

What functions do microglia carry out during homeostasis?

They monitor the extracellular environment, prune synapses, phagocytose surplus neural precursor cells, and support neurogenesis and neuronal health

What are the main immune functions of microglia?

• Phagocytosis – engulf pathogens/apoptotic cells

• Antigen presentation – activate T-cells via MHC-II

• Cytokine/chemokine release – mediate inflammation and immune recruitment

• Immunosurveillance – detect threats via extra/intracellular receptors

What neuronal functions do microglia support?

Neurogenesis, induction of apoptosis, clearance of apoptotic neurons, synaptic pruning, circuit maturation, and overall neuronal health maintenance

How do defects in microglial pruning affect neurodevelopment?

Impaired pruning can cause excess synapses, linked to autism spectrum disorders

What are the morphological forms of microglia?

• Ramified (resting) – branched, monitor environment

• Bushy – neurodegeneration, inflammation, toxicity

• Amoeboid (activated) – phagocytosis, motile, inflammatory response

What is the ultrastructure of microglia?

Elongated “bean-shaped” nuclei with peripheral heterochromatin, scattered rough ER/Golgi at poles, and astrocytic processes separating them from neurons.

How do resting vs activated microglia differ?

Resting = surveillance, synaptic maintenance. Activated = amoeboid, motile, phagocytic, can be protective or destructive.

What are M1 vs M2 microglia phenotypes?

• M1: Activated by LPS/IFN-γ, release pro-inflammatory cytokines, oxidative species, cause neurotoxicity.

• M2: Activated by IL-4/IL-13, release anti-inflammatory cytokines, promote repair, neuroprotection, and growth.

How do microglia detect injury?

Via membrane receptors, triggering chemokine release, proliferation, monocyte recruitment across the BBB, and motility.

What molecular markers are used for microglia?

IBA1 (general microglia), CD68 (activated microglia), DAPI (DNA, stains cell body)

What are Toll-like receptors (TLRs), and what do microglia use them for?

TLRs are pattern recognition receptors that detect PAMPs (e.g., viral RNA, bacterial LPS) and DAMPs (e.g., mitochondrial DNA, α-synuclein), triggering innate immune signaling.

What is the risk of microglial overactivation?

Excess release of ROS, NO, TNF-α → neurotoxicity. Overactivation contributes to Alzheimer’s, Parkinson’s, MS.

How do microglia contribute to Parkinson’s disease?

α-Synuclein aggregates activate microglia, leading to DA neuron destruction in the substantia nigra

What are the main differences between oligodendrocytes and Schwann cells?

Oligodendrocytes (CNS) myelinate multiple axons; Schwann cells (PNS) myelinate one axon each

What are the stages of oligodendrocyte differentiation?

OPCs (precursors) → immature oligodendrocytes → mature myelinating oligodendrocytes (regulated by transcription factors, growth factors, axonal signals)

What is the molecular process of myelination?

MBP traffics to myelin membranes, compacts cytoplasm, and drives wrapping; actin cytoskeleton rearrangements control membrane extension and adhesion

What are myelin incisures?

Narrow cytoplasmic channels within compact myelin that allow transport and communication between layers

What evolutionary advantage does myelination provide?

Enables rapid saltatory conduction, reduced axon diameter, energy efficiency, and supported the evolution of large, complex animals and behaviors

How much of the axonal membrane surface is available for ion exchange in myelinated fibers?

Less than 0.5%, concentrating ion flux at nodes of Ranvier

How is conduction achieved in myelinated axons?

Saltatory conduction – APs jump node to node, increasing speed and efficiency

What is the structural organization of myelinated axons?

Node of Ranvier (Na⁺ channels), paranode (Caspr, Contactin), juxtaparanode (K⁺ channels, Caspr2)

What role do adhesion molecules play in node assembly?

Neurofascin-186 and NrCAM cluster sodium channels at nodes, stabilizing conduction sites

How do oligodendrocytes metabolically support axons?

They deliver lactate/pyruvate through MCT1 (oligos) → MCT2 (axons) and glucose via GLUT1, fueling ATP for axonal function

What role does glutamate play in oligodendrocyte signaling?

Axons release glutamate at axo-glial synapses, activating AMPA/NMDA receptors on oligodendrocytes to regulate myelination

How do NMDA receptors differ in oligodendrocytes vs neurons?

Oligodendrocyte NMDA receptors lack strong Mg²⁺ block, remaining active at resting potential

What is excitotoxicity in oligodendrocytes?

Excess glutamate overstimulates receptors, causing ROS release, cytochrome c release, apoptosis via p38 MAPK, leading to demyelination

What clinical disorders involve oligodendrocyte/myelin dysfunction?

MS (autoimmune demyelination), cerebral palsy (perinatal white matter injury), schizophrenia (abnormal connectivity), Alzheimer’s (white matter loss)

What synaptic-like connections do OPCs form before differentiation?

They make direct neuron-OPC contacts, allowing neurons to regulate OPC proliferation and myelination timing