AXONAL TRANSPORT

 

INTRODUCTION:

The primary function of the retinal ganglion cell (RGC) axon is in conduction of action potentials. However, it also allows the cell body to communicate metabolically with its terminal neuronal targets in the lateral geniculate nucleus and the superior colliculus.

 

Axonal transport or axonal flow refers to the movement of axoplasmic material contained in the axons (and dendrites) in a predictable, energy-dependent manner. This movement has been shown to have fast and slow components, although numerous intermediate rates may also exist. Axonal transport is a basic physiologic phenomenon, common to neurons of all species; it has presumably evolved to enable neurons to maintain their extremely long, attenuated peripheral axons

The flow of axoplasm occurs in two different directions, namely, orthograde (from retina to lateral geniculate body) or retrograde (lateral geniculate body to retina). Orthograde transport refers to the movement of assembled materials or needed molecules distally to peripheral sites along the axon where they are required for membrane maintenance, growth or synaptic transmission. Retrograde transport refers to the movement of molecules or materials from peripheral sites back to the cell body.

 

These processes are instrumental in determining neuronal survival in development and disease. This communication is achieved by the transport of molecules, vesicles, and organelles in both an anterograde (also known as orthograde; from retina to lateral geniculate body) or retrograde (lateral geniculate body to retina) directions.

Anterograde/orthograde transport can be divided into the following processes:

1. Fast anterograde transport occurs at a rate of 50–400mm/day and is related to the transport of synaptic vesicles proteins, kinesins, and enzymes involved in the metabolism of neurotransmitters. 
2. Slow anterograde transport is given over to the transport of neuronally synthesised proteins that include cytoskeletal components, polymers, and protein complexes that are to be delivered to the axon and its terminal regions. It is divided into two types: slow axonal transport component A (SCa) (0.3–3 mm/day), which is concerned with the transport of neurofilament triplet proteins such as tubulin and spectrin (as well as tau proteins). The other system, slow axonal transport component B (SCb), is slightly faster (2–8 mm/day) and is concerned with the transport of microfilaments, actin, and supramolecular complexes of cytosolic matrix proteins.

The molecular motor for anterograde transport is provided by kinesin molecules that are part of a family of specialized motor proteins. Kinesins have a conserved motor domain that hydrolyses ATP to generate movement along the microtubules running down the axon. The kinesins are synthesized in the cell body and stored in a soluble form in the cytoplasm. The kinesin motor is activated on binding to the ’cargo’ molecule (the molecule or cellular component to be transferred along the axon), which then tracks along the axonal microtubules to the axon tip.

Retrograde transport is classed as fast (200–400 mm/day) and is concerned with the movement of endosomes and lysosomes containing internalized membrane receptors and neurotrophins towards the cell body. It uses dynein as the molecular motor. For the slower retrograde transport, the dynein is associated with actin–spectrin meshwork within the axon.

EXPERIMENTAL MODELS OF AXOPLASMIC FLOW:

Animal models (usually in monkeys) have been developed for studying axoplasmic flow by injecting radioactive amino acids, such as titrated leucine, into the vitreous.

The amino acid gets incorporated into RGCs by protein synthesis and then moves down the ganglion cell axon into the optic nerve. This allows histologic study of the orthograde movement of radioactively labeled protein.

Retrograde flow can be studied by observing the accumulation of certain unlabeled neuronal components, such as mitochondria by electron microscopy, or by injecting tracer elements, such as horseradish peroxidase into the lateral geniculate body and studying its movement toward the retina. These models can be used to study factors that cause abnormal blockade of axoplasmic flow, which may relate to glaucomatous optic atrophy in the human eye.

INFLUENCE OF IOP ON AXOPLASMIC FLOW:

Studies in monkey eyes have shown that raised IOP leads to obstruction of axoplasmic flow at the lamina cribrosa and the edge of the posterior scleral foramen. Chronically raised IOP decreases axonal transport preferentially in the magnocellular layers of the dorsal lateral geniculate nucleus, to which the large RGCs project.

In monkey eyes, the obstruction to fast axonal transport preferentially involves the superior, temporal, and inferior portions of the optic nerve head. The height and duration of pressure elevation influence the onset, distribution, and degree of axoplasmic obstruction in the optic nerve head.

The mechanism by which elevated IOP leads to obstruction of axoplasmic flow is uncertain, but there are two popular theories: mechanical and vascular.

The mechanical theory is based on the concept of physical alterations in the optic nerve head (ONH) leading to misalignment of the fenestrae in the lamina cribrosa which causes axoplasmic flow obstruction. This hypothesis is supported by the observation that axonal transport block occurs despite intact nerve head capillary circulation and an elevated arterial pO2. Axoplasmic transport is also affected in hypotonic states, suggesting that the pressure differential across the ONH, rather than a relative increase or decrease in IOP, causes mechanical changes which compress the axonal bundles. Additionally, a study of pig optic nerve has shown greater disruption of axoplasmic flow in the peripheral axons of the ONH, which suggests a mechanical element as the primary cause of this disruption.

Other studies did not find elevated intracranial pressure in monkeys caused obstruction of rapid axoplasmic flow nor prevented it in response to elevated IOP, despite reduction in the pressure gradient across the lamina. This suggests that more than a simple mechanical or hydrostatic mechanism may be involved with obstruction of axoplasmic flow in response to elevated IOP. It is also observed that axon damage is diffuse within bundles, rather than focal, as might be expected if a kinking effect was the primary culprit. Also, the location of transport interruption does not correlate with the cross-sectional area of fiber bundles, the shape of the laminar pores, or the density of interbundle septa.

The vascular theory is based on the premise that ischemia affects axoplasmic flow. Studies have shown that blockage of short posterior ciliary arteries and central retinal artery blocks both slow and fast axoplasmic flow, however, it did not cause glaucomatous cupping.

CONCLUSION:

While axoplasmic flow is considerably affected in some glaucoma patients it is not conclusive whether it is a primary factor in the development of glaucomatous damage and how it is affected in glaucoma. It can be argued that factors other than, or in addition to, ischemia and kinking of axons by a multilayered lamina cribrosa are involved in the IOP-induced obstruction to axoplasmic flow.