Glial Cells & Myelin

For a long time, glial cells were considered the supporting cast of the nervous system — the cells that filled the space around neurons, gave structural support, and produced myelin. That view is now obsolete. Glial cells participate actively in every aspect of neural function: they regulate the synapse, control the blood-brain barrier, modulate signaling between neurons, mount the brain’s immune response, and produce the myelin that enables fast conduction along axons. Many neurological diseases — multiple sclerosis, leukodystrophies, glioblastoma, neuromyelitis optica — are primarily diseases of glial cells. Understanding glia is therefore not an addendum to neuroanatomy; it is part of its core.

This page covers the five principal glial cell types of the nervous system, the structure and function of myelin, and the major glial diseases. The point is to give the trainee a working understanding of the cells that make up the majority of the brain’s volume and a substantial fraction of its function.

The Five Glial Cell Types

Astrocytes

Astrocytes are star-shaped cells, the most numerous glial cell type in the CNS. Their processes contact essentially every part of the nervous system — neurons, synapses, blood vessels, the pial surface. Several functional roles:

• Structural and metabolic support: astrocytes form a scaffold that organizes neuronal connections. They supply lactate as an alternative energy substrate to neurons (the astrocyte-neuron lactate shuttle hypothesis), buffer extracellular potassium, and clear glutamate from the synaptic cleft via the EAAT transporters.
• Blood-brain barrier participation: astrocyte endfeet wrap around cerebral capillaries, contributing to the structural integrity and signaling of the BBB. Loss of astrocyte-endothelial signaling disrupts barrier function.
• Tripartite synapse: each chemical synapse in the CNS is now understood to involve three cellular elements — the presynaptic neuron, the postsynaptic neuron, and an astrocyte process that wraps around them. Astrocytes detect neurotransmitter release, modulate synaptic strength, and signal back to neurons through gliotransmitters (ATP, glutamate, D-serine).
• Glymphatic system: astrocyte endfeet form the perivascular space that conducts CSF-interstitial fluid exchange, particularly during sleep, clearing metabolic waste from the brain.
• Reactive astrogliosis: in response to injury, astrocytes become hypertrophic, upregulate GFAP (the marker protein used in immunohistochemistry), and form a glial scar. This response limits the spread of damage but also inhibits neuronal regeneration, contributing to the poor recovery of CNS injury.

Astrocyte tumors (astrocytomas, including glioblastoma multiforme) are the most common primary CNS tumors in adults. Their grade reflects the degree of cellular atypia and proliferation; glioblastoma is the most aggressive form, with median survival measured in months despite multimodal therapy.

Oligodendrocytes

Oligodendrocytes are the myelin-producing cells of the CNS. A single oligodendrocyte may myelinate segments of up to 40 different axons, contrasting with the PNS, where each Schwann cell myelinates only one axon segment.

The myelin sheath consists of concentric layers of cell membrane wrapped tightly around the axon. Each layer is membrane lipid (about 70%) and protein (30%), with the major proteins being myelin basic protein (MBP), proteolipid protein (PLP), and myelin-oligodendrocyte glycoprotein (MOG). MOG is the antigen targeted in MOG antibody disease; the aquaporin-4 channel on astrocyte endfeet is the antigen in neuromyelitis optica.

The myelin sheath is interrupted at regular intervals (the nodes of Ranvier) where the axon is exposed and where voltage-gated sodium channels are concentrated. Action potentials “jump” from node to node — saltatory conduction — increasing conduction velocity tenfold or more compared with unmyelinated axons of the same diameter.

Schwann Cells

The PNS counterpart of oligodendrocytes. Unlike oligodendrocytes, each Schwann cell myelinates only a single segment of a single axon. Schwann cells also support unmyelinated axons (where many small unmyelinated axons may be embedded in a single Schwann cell as Remak bundles) and play a critical role in peripheral nerve regeneration after injury.

Several PNS diseases involve Schwann cells:

• Charcot-Marie-Tooth disease type 1: PMP22 gene duplications producing chronic demyelinating peripheral neuropathy.
• Guillain-Barré syndrome: acute autoimmune demyelinating polyradiculoneuropathy targeting the peripheral myelin.
• Schwannoma: benign tumor of Schwann cells, the most common being the vestibular schwannoma at the cerebellopontine angle.
• Neurofibromatosis type 1 and 2: genetic disorders predisposing to schwannomas and other tumors.

Microglia

Microglia are the resident immune cells of the CNS — the brain’s macrophages. They derive from mesoderm (specifically from yolk sac progenitors during embryonic development) rather than neural crest or neuroectoderm. In healthy brain, microglia continuously survey their environment with mobile processes, monitoring for injury or infection.

Microglia have several functional states:

• Surveillance (homeostatic): ramified morphology with mobile processes, continuously sampling the environment.
• Activation (M1-like, pro-inflammatory): amoeboid morphology, phagocytosis of debris and pathogens, release of pro-inflammatory cytokines.
• Activation (M2-like, anti-inflammatory): tissue repair, debris clearance, release of growth factors.

Microglial dysfunction is implicated in many neurological diseases:

• Alzheimer disease: microglia around amyloid plaques fail to clear them effectively; activated microglia contribute to neuroinflammation.
• Multiple sclerosis: microglia and macrophages participate in demyelination.
• HIV-associated neurocognitive disorder: HIV-infected microglia are the primary CNS reservoir of the virus.
• Frontotemporal dementia: TREM2 mutations affect microglial function and predispose to FTD.

Ependymal Cells

Ependymal cells line the ventricles of the brain and the central canal of the spinal cord. They are ciliated, with the cilia beating to propel CSF along the ventricular system. Specialized ependymal cells form the choroid plexus, which produces CSF (about 500 mL per day).

Disorders involving ependymal cells:

• Ependymoma: a tumor arising from ependymal cells, most commonly in the fourth ventricle in children. May produce obstructive hydrocephalus.
• Aqueductal stenosis: narrowing of the cerebral aqueduct, often congenital, sometimes associated with ependymal proliferation, producing non-communicating hydrocephalus.
• Ventriculitis: inflammation of the ependymal lining, often a complication of meningitis or ventricular shunt infection.

Myelin Structure and Function

The myelin sheath is a compact, lipid-rich, multilayered membrane that insulates axons. Properties of myelinated nerve fibers:

• Fast conduction: up to 100 m/s for the largest myelinated fibers, compared with 1-2 m/s for unmyelinated fibers.
• Saltatory conduction: action potentials regenerate only at the nodes of Ranvier, “jumping” between nodes. Energy-efficient (only the nodal membrane needs to repolarize).
• Insulation: minimizes ion leak across the internode, allowing tight clustering of axons without electrical interference.

The composition of myelin: about 70% lipid (cholesterol, galactocerebroside, sulfatides, phospholipids) and 30% protein. The major proteins differ between CNS and PNS:

Demyelinating Diseases

Multiple Sclerosis

The most common demyelinating disease. An autoimmune disorder targeting CNS myelin, with relapsing or progressive episodes of inflammation, demyelination, and (over time) axonal loss. Plaques are typically located in the optic nerve, periventricular white matter, brainstem, cerebellum, and spinal cord. The clinical course can be relapsing-remitting (the most common form), secondary progressive (eventual conversion from relapsing-remitting), or primary progressive (steady decline from onset). Disease-modifying therapies target the inflammatory component.

Neuromyelitis Optica Spectrum Disorder (NMOSD)

An autoimmune disease targeting aquaporin-4 (AQP4) on astrocyte endfeet, especially in the optic nerves and spinal cord. Distinct from MS in pathology, treatment response, and prognosis. AQP4 antibody testing distinguishes NMOSD from MS, which has major treatment implications (some MS medications, including interferon-beta, may worsen NMOSD).

MOG Antibody Disease

A newer recognized demyelinating disease targeting myelin oligodendrocyte glycoprotein. Often presents with optic neuritis, transverse myelitis, or ADEM-like episodes. Distinct from both MS and NMOSD.

Acute Disseminated Encephalomyelitis (ADEM)

A monophasic demyelinating illness, often postinfectious or post-vaccination, more common in children. Multiple white matter lesions appear simultaneously with the clinical onset, in contrast to MS where lesions accumulate over time.

Leukodystrophies

Genetic disorders affecting myelin development or maintenance:

• Adrenoleukodystrophy: X-linked, very long chain fatty acid accumulation, affecting the corticospinal tracts and adrenal glands.
• Metachromatic leukodystrophy: arylsulfatase A deficiency, with sulfatide accumulation.
• Krabbe disease: galactocerebrosidase deficiency, infantile onset.
• Pelizaeus-Merzbacher disease: PLP gene mutations, hypomyelinating from infancy.
• Vanishing white matter disease: mutations in EIF2B subunits.
• Alexander disease: GFAP mutations, astrocyte dysfunction with secondary white matter abnormalities.

Central Pontine Myelinolysis (Osmotic Demyelination Syndrome)

Demyelination of the pons (and sometimes extrapontine structures) following rapid correction of severe hyponatremia. Clinical presentation: pseudobulbar palsy, quadriparesis, sometimes locked-in syndrome. Recognition matters because the condition can be prevented by slow correction of sodium.

Glial Tumors

Tumors arising from glial cells (gliomas) are the most common primary brain tumors:

• Astrocytomas: grade 1 (pilocytic) through grade 4 (glioblastoma). Glioblastoma is the most common and most aggressive primary brain tumor in adults.
• Oligodendrogliomas: characterized by 1p/19q codeletion, which is associated with improved prognosis and chemotherapy response.
• Ependymomas: from ependymal cells, often pediatric, often in the fourth ventricle.
• Subependymal giant cell astrocytoma (SEGA): associated with tuberous sclerosis complex.

The 2021 WHO classification of CNS tumors incorporates molecular features prominently, with IDH mutation status, 1p/19q codeletion, MGMT promoter methylation, and several other markers determining diagnosis and treatment.

Glial Inflammation in Neurodegeneration

Chronic neuroinflammation involving microglia and astrocytes is now recognized as a key feature of essentially every neurodegenerative disease. In Alzheimer disease, microglia surrounding amyloid plaques and astrocytes near tau tangles contribute to neuronal injury. In Parkinson disease, microglial activation precedes neuronal loss. In ALS, glial cells expressing mutant SOD1 contribute to motor neuron death. The therapeutic implication — that targeting glial inflammation might modify neurodegenerative diseases — is the subject of active investigation.

🔍 Did You Know?

Myelin proteins are highly antigenic — among the most immunogenic in the body. When CNS myelin is exposed to the systemic immune system (as in experimental models or in certain disease states), a robust autoimmune response can be triggered. This is the basis of the classical experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), produced by immunizing animals with myelin proteins (typically MOG, PLP, or MBP). The intact blood-brain barrier normally prevents this exposure; one current hypothesis of MS pathogenesis posits that early subtle BBB disruption allows myelin antigens to leak out and prime an autoimmune response that then attacks the CNS.

Pitfalls and Pearls

• Astrocytes participate in the tripartite synapse and are active partners in neural signaling, not passive support cells.
• Oligodendrocytes myelinate multiple axon segments; Schwann cells myelinate only one. The distinction is fundamental to understanding CNS vs PNS demyelinating diseases.
• Microglia are the brain’s resident immune cells, derived from mesoderm (yolk sac), not neural crest. They are implicated in essentially every neurological disease.
• NMOSD targets aquaporin-4 on astrocyte endfeet, not myelin directly. This distinguishes it from MS and changes the treatment approach.
• MOG antibody disease is distinct from both MS and NMOSD, with characteristic clinical features (optic neuritis often bilateral, ADEM-like episodes) and different treatment considerations.
• Glioblastoma is the most common malignant primary brain tumor in adults, with median survival under 18 months despite optimal therapy.
• Central pontine myelinolysis is prevented by slow correction of hyponatremia — generally no more than 8-10 mEq/L in 24 hours.
• The molecular classification of gliomas (IDH mutation, 1p/19q codeletion, MGMT methylation) is now central to diagnosis and treatment decisions.
• Astrocytic glial scarring inhibits CNS regeneration — one reason for the limited recovery of CNS injury compared with PNS injury.
• Chronic glial inflammation is now recognized as a feature of essentially every neurodegenerative disease. Therapeutic targeting of glia is under active investigation.

References

1. Kettenmann H, Ransom BR, eds. Neuroglia. 3rd ed. Oxford University Press; 2013.
2. Verkhratsky A, Butt A. Glial Physiology and Pathophysiology. Wiley-Blackwell; 2013.
3. Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci. 2008;31:247-269.
4. Salzer JL, Zalc B. Myelination. Curr Biol. 2016;26(20):R971-R975.
5. 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.
6. Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46(6):957-967.