Glia II

Oligodendrocytes
- Primarily found in the Central Nervous System (CNS).
- Each oligodendrocyte myelinates multiple axons, averaging around 10 axons per cell.
Schwann Cells
- Can be classified into myelinating and non-myelinating Schwann cells.
- Myelinating Schwann cells wrap around single axons for insulation.
Myelination and Axonal Diameter
- Myelination is influenced by the diameter of the axon; conversely, the growth of axons is dependent on myelin sheath development.
- The relationship between the axonal diameter and the myelin sheath is characterized by the g-ratio (the ratio of the diameter of the axon to the diameter of the myelin sheath).
- This g-ratio generally has a consistent relationship of approximately 1:10 in both CNS and Peripheral Nervous System (PNS).
Interdependence Between Glia and Axons
- Loss of axons can lead to degeneration of oligodendrocytes and de-differentiation of Schwann cells.
- Conversely, axons may degenerate without proper support from Schwann cells and oligodendrocytes.

Non-myelinating Schwann cells provide support and insulation for bundles of small-diameter neurons.
They help maintain the health of myelinated axons and express surface markers such as L1 and NCAM, which are absent in myelinating Schwann cells.
Perisynaptic Schwann Cells (located at the Neuromuscular Junction (NMJ)) ensheath axonal terminal boutons and respond to synaptic activity through calcium (Ca2+) waves.
They play roles in modulating synaptic activities by regulating extracellular ion levels and inducing post-synaptic acetylcholine receptor aggregation.
Source: Glial neurobiology by Verkhratsky and Butt 2007.

OBECs are similar to non-myelinating Schwann cells but specifically ensheath the axons of the olfactory nerve.
Located at the junction of the CNS and PNS, they play a critical role in phagocytosing axonal debris and dead cells.
Their functions include supporting and guiding the growth of olfactory axons through glial scars and secreting numerous neurotrophic factors.
OBECs express glial markers, including GFAP, S100, and p75, along with radial glial markers like nestin and vimentin.

The myelin sheath consists of fatty layers that insulate axons, facilitating saltatory conduction.
It is composed of concentric layers of lamellae wrapped around individual axons.

Longitudinally, myelin sheaths are separated by nodes of Ranvier, which are specialized naked areas of axons where action potentials can propagate.
The segments of myelin between these nodes are referred to as internodes.

Important molecular interactions occur at paranodes and juxtaparanodes, leading to the clustering of potassium (K+) and sodium (Na+) channels crucial for saltatory conduction.

Lipids make up about 70% of myelin; cholesterol is the primary lipid component, with a composition of phospholipids and glycolipids in a ratio of 4:3:2.
Glycosphingolipids are abundant in myelin, notably GalC, which serves as a marker.
Different gangliosides are found in the CNS vs. PNS: CNS features ganglioside GM4, while PNS has LM1 and GM3.

Proteins constitute approximately 30% of myelin, largely shared between CNS and PNS myelin.
In the CNS, key proteins include MBP (Myelin Basic Protein) and PLP (Proteolipid Protein), which assist in fusing the extracellular and cytoplasmic faces of the myelin sheath.
In the PNS, the primary protein is P0, which mediates the fusion of lamellae, along with other important proteins such as PMP22 and Cx32.
MAG (Myelin-Associated Glycoprotein) is present in both myelin types and is important for axon-myelin interaction by binding to specific gangliosides on the axonal surface.

Phase 1: Axon Contact
- Occurs when an axon grows thicker than 0.7 mm in the PNS or 0.2 mm in the CNS.
- Loss of NCAM from the axonal surface initiates myelination.
- The expression of the surface marker L1 indicates axons are ready for myelination, marking them for myelination.
- Contact with axons stimulates the differentiation of oligodendrocyte precursor cells (OPCs) into oligodendrocytes, leading to the expression of myelin products such as GalC, CNP (Contactin-associated protein), and MBP.
- Source: Glial neurobiology by Verkhratsky and Butt 2007.
Phase 2: Axon Ensheathment and Establishment of Internodal Segments
- Involves the extension of an initiator process that spirals around the axon, utilizing MAG and PLP for ‘stitching’ the myelin segments.
- This phase includes the myelination of multiple axons, followed by a remodeling phase characterized by the loss of non-ensheathing processes and initial clustering of sodium channels at the nodes of Ranvier.
- Source: Glial neurobiology by Verkhratsky and Butt 2007.
Phase 3 and 4: Remodeling and Maturation
- The production of subsequent myelin wraps occurs, fusing with each other reliant on proteins PLP and MBP.
- Maturation of nodes of Ranvier corresponds with synchronized expression of molecular pairs at both axon and myelin.

Autoimmunity: The immune system undergoes an autoimmune response against the CNS, leading to the formation of plaques or lesions.
- Auto-antibodies against myelin components are generated, commonly involving the white matter.
- Direct damage occurs to oligodendrocytes, causing demyelination, with potential for early-phase remyelination but often incomplete.
- Relapses in the disease lead to impaired remyelination.
Blood-Brain Barrier (BBB) Breakdown: Damage to the BBB facilitates the entry of immune cells, predominantly T cells.
- Chronic inflammation results from T cells attacking myelin, which recruits other inflammatory cells through the release of cytokines and antibodies.
- BBB leakage leads to swelling and the activation of macrophages, creating a cycle of inflammation and damage exacerbated by astrocytes and microglia.
- Source: Dendrou et al. 2015.

Early Disease Stage:
- Infiltration of immune cells from the periphery into the CNS occurs.
- Soluble mediators recruit immune cells, including CD8+ and CD4+ T cells.
- Activation of perivascular immune cells accumulates, leading to chronic CNS inflammation.
Late Disease Stage:
- Clonal expansion of B cells occurs along with T cell reactivation, resulting in formation of tertiary lymphoid structures that further damage the glial limitans and affect astrocytic function.
- Consequences include neuroaxonal damage as metabolic stress, and energy deficiency promote further damage at distal sites.
- Source: Dendrou et al. 2015.

The similarities and differences between Schwann cells and oligodendrocytes are significant in understanding their respective roles in myelination.
Basic structure-function relationship of myelin plays a pivotal role in facilitating neuronal communication.
The crosstalk between axons and myelinating cells is fundamental in defining the processes of myelination.
The interaction between oligodendrocytes (and oligodendrocyte progenitor cells (OPCs)) with other glial cells is crucial in determining the progression of demyelinating diseases.