Neurohistology & Glial Cells
Neurohistology & Glial Cells
What Do You Need to Know?
- 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
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 | 200–300 mm/day |
| 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 / vinca alkaloids block microtubules | NGF, BDNF; exploited by rabies, herpes, poliovirus, tetanus toxin |
Board Pearl
Rabies, herpes simplex, poliovirus, and tetanus toxin all exploit retrograde axonal transport (dynein) to reach the CNS. 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, S-100 | BBB (foot processes), glutamate uptake (EAAT2), K⁺ buffering, glycogen storage, scar formation | Reactive gliosis; astrocytoma / GBM |
| Oligodendrocytes | CNS | Neuroectoderm | MBP, PLP, MOG | CNS myelination; 1 cell : up to 50 axon segments | MS; oligodendroglioma |
| Schwann cells | PNS | Neural crest | S-100, P0, PMP22 | PNS myelination; 1 cell : 1 internode; bands of Büngner | GBS, CIDP, CMT; schwannoma |
| Microglia | CNS | Mesoderm (bone marrow) | CD68, Iba1 | Resident macrophages; immune surveillance, phagocytosis | Activated in neurodegeneration; primary CNS lymphoma |
| Ependymal cells | CNS (ventricles) | Neuroectoderm | S-100 | Line ventricles; ciliated (CSF flow); choroid plexus produces 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 — mesodermal / bone marrow origin
- Resting: ramified; Activated: amoeboid, phagocytic; release TNF-α, IL-1, IL-6
- 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.
Myelination
Myelin Composition & Structure
- Composition: ~70% lipid, ~30% protein (highest lipid-to-protein ratio of any biological membrane)
- Lipids: cholesterol, galactocerebroside, sulfatides, phospholipids, plasmalogen
- Nodes of Ranvier: gaps between myelin sheaths; high density of Nav1.6 channels → saltatory conduction
- Paranodal K⁺ channels: normally covered; exposed in demyelination → K⁺ leak → conduction failure
CNS vs PNS Myelin Proteins
| Protein | Location | Function | Clinical Significance |
|---|---|---|---|
| MBP | CNS + PNS | Compacts cytoplasmic faces | Target in EAE (animal model of MS) |
| PLP | CNS only | Most abundant CNS myelin protein | PLP1 mutation → Pelizaeus-Merzbacher disease |
| MOG | CNS only (outermost) | Structural integrity | MOG antibodies → MOGAD (optic neuritis, ADEM) |
| MAG | CNS + PNS | Axon-glia interaction; inhibits CNS regeneration | Anti-MAG neuropathy (IgM); widened myelin lamellae |
| P0 | PNS only | Most abundant PNS myelin protein | P0 mutation → CMT1B |
| PMP22 | PNS only | Myelin compaction | Duplication → CMT1A; Deletion → HNPP |
Myelination Timeline
- Begins: 2nd trimester (PNS before CNS)
- Progression: caudal → rostral, posterior → anterior; brainstem myelinated at birth, cortex incomplete
- Continues: into mid-20s (prefrontal cortex last)
- MRI: T1 brightens and T2 darkens as myelination progresses in infancy
Board Pearl
PMP22 duplication = CMT1A (most common CMT); PMP22 deletion = HNPP. PLP1 mutation = Pelizaeus-Merzbacher (X-linked). P0 = most abundant PNS myelin protein; PLP = most abundant CNS myelin protein. MOG antibodies cause MOGAD, distinct from MS and AQP4+ NMOSD.
Demyelination vs Dysmyelination
Key Distinction
- Demyelination: destruction of previously normal myelin (acquired, immune-mediated or toxic)
- Dysmyelination: defective myelin formation from the start (hereditary enzyme or structural protein deficiency)
Comparison Table
| Feature | Demyelination (Acquired) | Dysmyelination (Hereditary) |
|---|---|---|
| Mechanism | Immune attack on normal myelin | Inherited defect in myelin synthesis |
| Onset | Usually adult (MS) or acute (GBS, ADEM) | Usually childhood |
| Course | Relapsing-remitting or monophasic | Progressive, often fatal |
| CNS examples | MS, NMOSD, MOGAD, ADEM, PML | Leukodystrophies (MLD, Krabbe, ALD, PMD) |
| PNS examples | GBS, CIDP | CMT1A, CMT1B, HNPP |
| MRI | Focal, asymmetric lesions | Diffuse, symmetric white matter changes |
Leukodystrophies — High-Yield Table
| Disease | Enzyme / Defect | Substrate | Inheritance | Key Features |
|---|---|---|---|---|
| Metachromatic (MLD) | Arylsulfatase A | Sulfatides | AR | Metachromatic granules; dementia, spasticity, peripheral neuropathy |
| Krabbe | Galactocerebrosidase | Psychosine (toxic) | AR | Globoid cells; irritability, spasticity, optic atrophy; rapid course |
| ALD | ABCD1 transporter | VLCFA | X-linked | Posterior → frontal WM; adrenal insufficiency; adult = AMN |
| Pelizaeus-Merzbacher | PLP1 mutation | Abnormal PLP | X-linked | Nystagmus, spasticity, ataxia; "tigroid" pattern |
| Alexander | GFAP mutation (GOF) | Rosenthal fibers | AD (de novo) | Megalencephaly, frontal predominance, seizures |
| Canavan | Aspartoacylase | NAA | AR | Megalencephaly, spongiform WM; elevated urine NAA; Ashkenazi |
Hereditary Demyelinating Neuropathies
- CMT1A: PMP22 duplication; NCV uniformly slow (<38 m/s); onion bulbs on biopsy
- CMT1B: P0 (MPZ) mutation; demyelinating
- HNPP: PMP22 deletion; recurrent compressive neuropathies; tomaculae on biopsy
Clinical Pearl
Leukodystrophies show diffuse, symmetric white matter changes on MRI — unlike MS (asymmetric, periventricular). ALD starts parieto-occipital and progresses anteriorly with a leading edge of enhancement. Alexander disease is the exception — frontal predominance.
Neuronal Degeneration & Regeneration
Wallerian Degeneration
- Definition: degeneration of axon and myelin distal to the site of injury
- 0–48 hours: distal axon and myelin begin to fragment
- 3–5 days: Schwann cells proliferate; macrophages infiltrate to clear debris
- 7–10 days: degeneration complete; NCS shows absent or reduced distal responses
- Schwann cells form bands of Büngner → guide regenerating axons
Chromatolysis
- Definition: cell body reaction to axonal injury (proximal response)
- Features: cell body swelling, nucleus displaced peripherally, Nissl substance dissolution
- Purpose: metabolic shift from neurotransmitter production to repair proteins
PNS vs CNS Regeneration
| Feature | PNS | CNS |
|---|---|---|
| Capacity | Good | Very poor |
| Rate | ~1 mm/day (~1 inch/month) | Minimal / absent |
| Support | Schwann cells → bands of Büngner + neurotrophic factors | Oligodendrocytes do not support regrowth |
| Inhibitors | Minimal | Nogo-A, MAG, OMgp, glial scar (CSPGs) |
| Guidance | Intact endoneurial tubes | No equivalent structure |
Board Pearl
CNS does not regenerate because of Nogo-A (oligodendrocytes), MAG, and astrocytic glial scar. PNS regenerates at ~1 mm/day via Schwann cell bands of Büngner. Chromatolysis = cell body swelling + peripheral nucleus + Nissl dissolution. Motor end plates degenerate by 12–18 months, setting a time limit for reinnervation.
Staining Methods
Neurohistological Stains
| Stain / Marker | Target | Clinical Use |
|---|---|---|
| Nissl (cresyl violet) | Rough ER in neuronal cell bodies | Neuron identification; lost in chromatolysis |
| Luxol fast blue (LFB) | Myelin phospholipids | Demyelination (pale areas = myelin loss) |
| Silver stains (Bielschowsky) | Axons, tangles, plaques | Alzheimer pathology |
| GFAP | Astrocytes | Astrocytoma, GBM, reactive gliosis |
| CD68 | Microglia / macrophages | Inflammation, infarction |
| S-100 | Schwann cells, astrocytes, melanocytes | Schwannoma (strongly positive) |
| Synaptophysin | Presynaptic vesicles | Neuronal / neuroendocrine tumors |
| NeuN | Neuronal nuclei | Mature neurons (absent in Purkinje cells) |
| Olig2 | Oligodendrocyte lineage | Oligodendroglioma, diffuse astrocytoma |
| EMA | Epithelial membrane antigen | Meningioma, ependymoma |
Clinical Pearl
On nerve biopsy: LFB stains myelin (pale = demyelination), toluidine blue semithin sections show onion bulbs (CMT1A), EM reveals widened myelin lamellae (anti-MAG neuropathy) or tomaculae (HNPP).
Tumors by Glial Cell of Origin
Cell of Origin → Tumor Type
| Cell of Origin | Tumor | Marker | High-Yield Features |
|---|---|---|---|
| Astrocyte | Astrocytoma / GBM | GFAP+ | GBM: pseudopalisading necrosis, ring enhancement; IDH-wildtype |
| Oligodendrocyte | Oligodendroglioma | Olig2+ | Fried egg cells, chicken-wire vessels; 1p/19q co-deletion; IDH-mutant |
| Ependymal cell | Ependymoma | EMA+, GFAP+ | Perivascular pseudorosettes; 4th ventricle (children), spinal cord (adults) |
| Schwann cell | Schwannoma | S-100+ | Antoni A/B pattern, Verocay bodies; CN VIII; bilateral = NF2 |
| Arachnoid cap cell | Meningioma | EMA+, vimentin+ | Psammoma bodies; dural-based, extra-axial; NF2-associated |
| Microglia | Primary CNS lymphoma | CD20+ (B-cell) | Perivascular cuffing; HIV/immunosuppression; "ghost tumor" with steroids |
Board Pearl
Oligodendroglioma = 1p/19q co-deletion + IDH-mutant; fried egg cells. GBM = pseudopalisading necrosis, IDH-wildtype. Schwannoma = S-100+, bilateral CN VIII = NF2. Primary CNS lymphoma arises from the perivascular microglia/macrophage niche — always think HIV/immunosuppression.
Quick Reference
High-Yield Summary Table
| Topic | Key Fact | Board Buzzword |
|---|---|---|
| Nissl substance | Rough ER; absent from axon hillock and axon | Chromatolysis = Nissl dissolution |
| Neuron types | Pseudounipolar in DRG; multipolar = most CNS | Bipolar = retina, vestibular, olfactory |
| Axonal transport | Kinesin (anterograde) vs dynein (retrograde) | Rabies, herpes, tetanus = retrograde |
| Astrocytes | BBB, glutamate uptake, K⁺ buffering, scar | GFAP+; Alzheimer type II in hepatic encephalopathy |
| Oligodendrocytes | CNS myelin; 1 cell : up to 50 axons | Destroyed in MS |
| Schwann cells | PNS myelin; 1 cell : 1 internode | Bands of Büngner; S-100+ |
| Microglia | Mesoderm origin; CNS macrophage | CD68+; HIV reservoir |
| Myelin | 70% lipid / 30% protein | PLP = CNS; P0 = PNS most abundant |
| CMT1A | PMP22 duplication; demyelinating | Onion bulbs on biopsy |
| MLD | Arylsulfatase A; sulfatides | Metachromatic granules |
| Krabbe | Galactocerebrosidase | Globoid cells |
| ALD | ABCD1; VLCFA | X-linked; parieto-occipital → frontal |
| Wallerian degen. | Distal axon dies; NCS changes 7–10 days | Fibrillations at 2–5 weeks |
| CNS regen. failure | Nogo-A, MAG, glial scar | PNS = 1 mm/day |
| GBM | GFAP+; IDH-wildtype | Pseudopalisading necrosis |
| Oligodendroglioma | 1p/19q co-deletion + IDH-mutant | Fried egg cells, calcification |
Board Pearl
Do not confuse demyelination (acquired destruction of normal myelin) with dysmyelination (hereditary defect in myelin formation). Leukodystrophies show diffuse, symmetric white matter changes — unlike MS (focal, asymmetric, periventricular). Alexander disease (GFAP mutation, Rosenthal fibers) and Canavan disease (aspartoacylase, elevated NAA) both cause megalencephaly — distinguish by frontal MRI predominance (Alexander) vs spongiform degeneration with elevated urine NAA (Canavan).
References
- Kandel ER, Schwartz JH, Jessell TM, et al. Principles of Neural Science. 6th ed. McGraw-Hill; 2021.
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw-Hill; 2023.
- Love S, Budka H, Ironside JW, Perry A. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
- Waxman SG. Clinical Neuroanatomy. 29th ed. McGraw-Hill; 2020.
- van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol. 2017;134(3):351–382.
- Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231–1251.