The Role of Retinal Ganglion Cell Myelination in Signal Conduction and Retinal Organization
Open AccessThe nervous system relies on effective neural signaling to encode and transmit information as electrical signals called action potentials. In retinal ganglion cells (RGCs), the pattern of action potential firing is a compression of complex visual information, which travels along RGC axons, extending out of the eye and forming the optic nerve and tract before synapsing in cortical regions. The rapid communication is highly efficient, leveraging structural properties, such as fiber diameter, the insulative myelin sheath, and ion channel expression, to ensure signal transmission. In the central nervous system, oligodendrocytes produce the myelin sheath which promotes signal conduction by wrapping around axons, providing insulation, and concentrating ion channels at unmyelinated nodes of Ranvier. While myelination is an established regulator of axonal conduction, the functional role of its specific properties in the optic nerve is not well studied. Demyelination and inflammation can cause severe functional deficits, observed in diseases like multiple sclerosis and optic neuritis, where patients experience visual deficits and thinning of retinal layers containing RGCs and their contacts. However, the impact of RGC demyelination on the survival of retinal networks remains unclear. The current studies explore structure-function relationships in optic nerve conduction using compound action potentials (CAPs), morphological analysis, and computational modeling. Refinement of functionally-distinct axon populations in wildtype optic nerve CAPs correlated with altered myelin protein expression, decreased g-ratios, and maturation of sodium ion channels (Nav) between 4-12 postnatal weeks. Using experimental datasets, I simulated CAP responses to observe relationships between conduction velocity and Nav subtype expression, axon diameter, myelin thickness, and g-ratio. This analysis revealed Nav subtype as a potential functional regulator of axon populations, however axon diameter and myelin thickness were also relevant. Next, I found that targeted oligodendrocyte ablation in the MBP-iCP9 mouse model induced demyelination, reduced axon diameter, and disruptions to the slowest-conducting axon populations in the optic nerve. In the retina, this reduced αRGC and cholinergic amacrine cell populations, and thickness of the inner plexiform layer, indicating that demyelination can drive changes in the upstream retinal network. Identifying these demyelination-induced deficits is useful in developing therapeutics targeting neuronal loss in demyelinating disease.
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