Neurohistology & Glial Cells
Neurohistology & Glial Cells
What You'll Learn
- Neuron structure — Nissl substance (rough ER) absent from axon hillock and axon; axon hillock = AP initiation site
- Neuron classification — unipolar, bipolar, pseudounipolar (DRG), multipolar (most CNS neurons)
- Axonal transport — anterograde (kinesin) vs retrograde (dynein); rabies, herpes, and tetanus toxin travel retrograde
- Glial cells — astrocytes (BBB, GFAP+), oligodendrocytes (CNS myelin, 1:50), Schwann cells (PNS myelin, 1:1), microglia (mesoderm-derived), ependymal cells (line ventricles)
- Myelin composition — 70% lipid / 30% protein; CNS proteins (MBP, PLP, MOG, MAG) vs PNS proteins (P0, PMP22, MBP)
- Demyelination vs dysmyelination — acquired (MS, GBS) vs hereditary leukodystrophies (MLD, Krabbe, ALD, PMD)
- Degeneration & regeneration — Wallerian degeneration, chromatolysis, PNS regenerates (1 mm/day), CNS does not (Nogo, MAG)
- Staining methods & tumors — Nissl, Luxol fast blue, GFAP, silver stains; tumors arise from specific glial cell types
HighYield Pearls
- Axon hillock: AP initiation site — highest density of voltage-gated Na⁺ channels, lowest threshold; Nissl substance (rER) is ABSENT here and throughout the axon
- Kinesin = anterograde, Dynein = retrograde: rabies, HSV, poliovirus, and tetanus toxin exploit retrograde (dynein) transport to reach CNS/soma
- Astrocyte foot processes + AQP4: support and induce the BBB — the primary paracellular barrier is the cerebral endothelial tight junctions (with basement membrane and pericytes); astrocytic AQP4 is important for water handling and is the antibody target in NMOSD; GFAP is the astrocyte marker
- Oligodendrocyte vs Schwann ratio: one oligo myelinates many CNS internodes (1:up to 50); one Schwann cell myelinates ONE PNS internode (1:1)
- Microglia origin = mesoderm (yolk sac): the ONLY non-neuroectodermal glia; CNS resident macrophages — activated in HIV (microglial nodules + multinucleated giant cells), neurodegeneration; markers IBA1, CD68
- Rosenthal fibers: Alexander disease (GFAP mutation, frontal leukodystrophy, macrocephaly), pilocytic astrocytoma, chronic gliosis
- Chromatolysis: central Nissl loss + eccentric nucleus + swollen soma after AXONAL injury — signals attempted regeneration
- Wallerian degeneration: axon + myelin breakdown DISTAL to transection; PNS Schwann cells form BAND OF BÜNGNER to guide regen at ~1 mm/day; CNS does NOT regenerate (Nogo, MAG inhibition)
- Red (eosinophilic) neurons: earliest histologic marker of ischemic/hypoxic injury — shrunken pyknotic neurons within hours
- NfL (neurofilament light chain): serum/CSF biomarker of axonal damage — elevated in MS, ALS, AD, TBI
🔍 Quick ReferenceCell type / marker · Architecture / transport · Disease / inclusion
Cell type / marker
- GFAP⁺ → astrocyte (fibrous = white matter, protoplasmic = gray matter)
- MBP, PLP, MOG, MAG, OLIG2 → oligodendrocyte / CNS myelin (MOG = antibody in MOGAD)
- IBA1, CD68, CR3 → microglia (mesodermal / yolk sac origin)
- S100⁺, GAP43 (regen), P0, PMP22 → Schwann cell / PNS myelin
- Synaptophysin, chromogranin, NeuN, NSE, NCAM/CD56 → neuronal markers
- AQP4 antibody → NMOSD (targets astrocyte foot processes)
Architecture / transport
- Kinesin → anterograde axonal transport (soma → terminal; vesicles, mitochondria)
- Dynein → retrograde axonal transport (terminal → soma; NGF, viruses, toxins)
- Schmidt-Lanterman incisures → cytoplasmic clefts in PNS (Schwann) myelin
- Nodes of Ranvier → Nav clusters; paranodal Caspr/contactin/NF155, juxtaparanodal Kv1.1/1.2
- Remak bundles → unmyelinated C fibers ensheathed by ONE Schwann cell
- Band of Büngner → Schwann cell columns guiding PNS axonal regeneration
- Subventricular zone (SVZ) + subgranular zone (SGZ) → adult neurogenesis niches (SVZ → olfactory bulb; SGZ → dentate gyrus)
- Virchow-Robin (perivascular) spaces → astrocytic foot processes surrounding penetrating vessels
Disease / inclusion
- Rosenthal fibers → Alexander disease (GFAP mutation), pilocytic astrocytoma, chronic gliosis
- Gemistocytes → reactive astrocytosis / gliosis (plump eosinophilic astrocytes)
- Microglial nodules + multinucleated giant cells → HIV encephalitis
- Chromatolysis (central Nissl loss + eccentric nucleus) → axonal injury response in soma
- Red (eosinophilic) neurons → acute hypoxic-ischemic injury
- Band of Büngner → PNS Wallerian regeneration scaffold
- Schwannoma / bilateral vestibular schwannomas → NF2; neurofibroma / plexiform neurofibroma → NF1
- Negri bodies → rabies (cytoplasmic, hippocampus/Purkinje — retrograde transport entry)
Neuron Structure
Cell Body & Processes
- Nissl substance: rough ER + free polyribosomes; basophilic on staining; present in cell body and dendrites
- Nissl is absent from: axon hillock and axon → no local protein synthesis in the axon
- Axon hillock: lowest threshold for AP generation (highest density of voltage-gated Na⁺ channels)
- Dendrites: receive synaptic input; dendritic spines = sites of excitatory synapses
- Axon: single process; conducts AP away from soma; contains neurofilaments and microtubules for transport
Neuron Classification by Morphology
| Type | Processes | Location / Example |
|---|---|---|
| Unipolar | Single process | Rare in humans; invertebrate nervous systems |
| Bipolar | One axon + one dendrite | Retina, vestibular ganglion, olfactory epithelium |
| Pseudounipolar | Single process that bifurcates | Dorsal root ganglia (DRG), cranial nerve sensory ganglia |
| Multipolar | One axon + multiple dendrites | Most CNS neurons (motor neurons, pyramidal cells, Purkinje cells) |
Board Pearl
Nissl substance = rough ER; it is absent from the axon hillock and axon. Chromatolysis (dissolution of Nissl substance) occurs in the cell body after axonal injury. Pseudounipolar neurons in the DRG are often called "unipolar" on exams — they have a single process that splits into two branches.
Axonal Transport
Anterograde vs Retrograde Transport
| Feature | Anterograde | Retrograde |
|---|---|---|
| Direction | Soma → axon terminal | Axon terminal → soma |
| Motor protein | Kinesin (+ end of microtubules) | Dynein (− end of microtubules) |
| Fast rate | 200–400 mm/day | ~100–200 mm/day (approximately half the rate of fast anterograde) |
| Fast cargo | Vesicles, mitochondria, ion channels | Endosomes, lysosomes, signaling molecules |
| Slow rate | 1–5 mm/day | N/A |
| Slow cargo | Cytoskeletal proteins (neurofilaments, tubulin) | N/A |
| Clinical relevance | Colchicine and vinca alkaloids disrupt microtubule-based transport in BOTH directions (anterograde kinesin + retrograde dynein both require intact microtubules) | NGF, BDNF; exploited by rabies, herpes, poliovirus, tetanus toxin |
Board Pearl
Retrograde axonal transport pathogens: rabies (canonical), HSV (retrograde to ganglion for latency, anterograde for reactivation), tetanus toxin. Poliovirus reaches CNS primarily hematogenously; retrograde axonal transport contributory. Tetanus toxin travels retrograde to inhibitory interneurons, cleaves synaptobrevin → blocks GABA/glycine release → spastic paralysis.
Glial Cell Types
Master Comparison Table
| Glial Cell | Location | Origin | Marker | Key Functions | Pathology |
|---|---|---|---|---|---|
| Astrocytes | CNS | Neuroectoderm | GFAP (lead marker); AQP4 (NMOSD target); EAAT1 (GLAST) & EAAT2 (GLT-1) glutamate transporters; Kir4.1 (K⁺ buffering); S-100 (broader — also Schwann, melanocytes) | BBB (foot processes), glutamate uptake (EAAT2), K⁺ buffering, glycogen storage, scar formation | Reactive gliosis; astrocytoma / GBM |
| Oligodendrocytes | CNS | Neuroectoderm | Olig2 (lineage marker); MBP/PLP/MOG/MAG are myelin products (not cell-body IHC markers) | CNS myelination; 1 cell : up to 50 axon segments | MS; oligodendroglioma |
| Schwann cells | PNS | Neural crest | S-100, P0, PMP22 | Myelinating Schwann cell = 1 internode of 1 axon (1:1). Nonmyelinating Schwann cells (Remak cells) ensheath multiple unmyelinated axons in Remak bundles. Bands of Büngner. | GBS, CIDP, CMT; schwannoma |
| Microglia | CNS | Mesoderm — yolk-sac primitive macrophages (Ginhoux 2010); bone-marrow-derived monocytes can infiltrate CNS in pathology but are NOT the source of resident microglia | CD68, Iba1 | Resident macrophages; immune surveillance, phagocytosis | Activated in neurodegeneration |
| Ependymal cells | CNS (ventricles) | Neuroectoderm | S-100 | Line ventricles; ciliated (CSF flow). Choroid plexus epithelium (specialized modified ependyma) produces CSF; general ventricular ependymal cells do NOT produce CSF. | Ependymoma (4th ventricle in children) |
Astrocytes — Key Details
- Protoplasmic: gray matter; Fibrous: white matter
- BBB: foot processes wrap capillary endothelial cells; induce tight junctions
- Glutamate recycling: uptake via EAAT2 → glutamine synthetase → glutamine shuttled back to neurons
- K⁺ spatial buffering: redistribute excess extracellular K⁺ to prevent hyperexcitability
- Reactive gliosis: hypertrophy after CNS injury → glial scar (GFAP+); inhibits axonal regeneration
Microglia — Key Details
- Only glial cell NOT from neuroectoderm — yolk-sac primitive macrophage origin (mesoderm)
- Resting: ramified; Activated: amoeboid, phagocytic; release TNF-α, IL-1, IL-6
- Rod cells: elongated microglia — classic for neurosyphilis (also seen in subacute encephalitis)
- Gitter cells: lipid-laden foamy macrophages of chronic ischemia / infarct cavity
- HIV encephalitis: microglia = primary CNS reservoir for HIV; microglial nodules on pathology
Board Pearl
Microglia are the only glial cells derived from mesoderm (not neuroectoderm). All other glia (astrocytes, oligodendrocytes, ependymal cells) derive from neuroectoderm. Schwann cells derive from neural crest. Microglia are the primary CNS reservoir for HIV.
Clinical Pearl
Astrocyte dysfunction in hepatic encephalopathy: ammonia is converted to glutamine by glutamine synthetase in astrocytes → osmotic swelling → Alzheimer type II astrocytes (large, pale nuclei) on histology.
Osmotic demyelination syndrome (ODS / central pontine myelinolysis): rapid correction of chronic hyponatremia → astrocyte death precedes oligodendrocyte death (astrocytes are osmotically more vulnerable). The pattern reinforces that astrocyte–oligodendrocyte coupling underlies myelin integrity — primary astrocyte injury triggers secondary demyelination. Same principle applies to Alexander disease.
VEGF and BBB permeability: astrocyte-derived VEGF destabilizes the BBB in tumors, inflammation, and ischemia → vasogenic edema. Anti-VEGF therapy (bevacizumab) reduces edema in glioblastoma and radiation necrosis.
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