Retinal ganglion cells: Energetics, compartmentation, axonal transport, cytoskeletons and vulnerability
Introduction
All biochemical reactions involve energy exchange. A large quantity of internal free energy is therefore required for cell survival and function (Alberts B et al., 2002). The key forms of intracellular free energy are nucleotide triphosphates, such as ATP. ATP is produced by a series of chemical reactions and synthesized either by oxidative phosphorylation in mitochondria (approximately 90% of total) or by glycolysis in the cytosol. Roughly 109 molecules of ATP are present in a single cell at any instant and, in many cells, all of this ATP is used and replaced every 1–2 min (Alberts B et al., 2002).
It is estimated that ∼20% of total oxygen consumption in the human body occurs in the brain which constitutes only ∼2% of total body weight (Coyle and Puttfarcken, 1993). Arguably, the energy demands of retinal tissue are even greater than brain tissue, with estimates of oxygen consumption per tissue weight in the retina being one of the highest in the human body (Ames and Li, 1992).
RGCs are specialized projection neurons that convey visual information from the retina to the brain. 90% of all sensory signals that are integrated in the brain are of visual origin and almost a third of the cortical surface is devoted to visual processing (Chalupa and Werner, 2004). RGCs have a large cell body, relative to other retinal neurons, and these cell bodies are located along the inner margin of the retina, in the retinal ganglion cell layer. The biogenesis site of all organelles and cytoplasm is the cell body and for this reason the functional activity and survival of RGC axons and dendrites are dependent upon the RGC soma (Munemasa and Kitaoka, 2012).
The histological section shown in Fig. 1 is taken from the parafoveal region of a monkey retina where the RGC bodies are smaller than in the peripheral retina. The RGC cell body has a rich cytoplasm. Like most neurons, RGCs are polarized into dendritic and axonal compartments that are connected at the cell body. The molecular differences within a neuron that result in structural polarisation are also responsible for some degree of functional polarisation. In the RGC, signal inputs are collected by the dendrites and a pulse-coded signal is transmitted from the cell body via the axon. RGC dendrites extend into the inner plexiform layer (IPL), a neuropil located on the outer side of the RGC layer. Abundant synaptic contacts are located in the IPL. RGCs receive inputs from bipolar cells, which convey signals from photoreceptors to the IPL, and from amacrine cells that branch in the IPL (Fig. 1). There are approximately 20–30 subtypes of amacrine cells that are structurally diverse with respect to the distribution of their processes.
The visual stimulus is unique as it undergoes a tremendous amount of processing within retinal layers, encompassing the spatial and temporal properties of the light stimulus, prior to transmission by RGC axons to the brain (Hogan et al., 1971). More than 1 million RGC axons form the optic nerve, a vital structure that acts as a conduit between the retina and the brain. Most nerve axons are 0.5 μm or more in diameter and ∼50 mm in length. It is worth noting that axon fibres, which serve as the primary signal conduit in neurons, are on average ∼20,000 times larger than the cell body with respect to length and total surface area (Friede, 1963). The optic nerve contains 38% of all the afferent fibres contained in cranial nerves (Hogan et al., 1971).
Due to their unusually high energy requirements, retinal cells are exquisitely sensitive to disturbances in the supply of their energy sources (oxygen and other substrates). The density of the vascular network that is able to sustain such high metabolic demands is constrained by the requirement for relative optical transparency. Therefore, retinal cells can only be served by a limited blood supply and this anatomical constraint predisposes the retina to a range of vascular diseases. The delicate balance between oxygen availability and consumption can only be achieved by precise regulatory mechanisms that serve to match local blood flow with local tissue demands. Even minor disruptions of these homeostatic mechanisms can have severe deleterious consequences in the retina.
This review sets out to elucidate how RGCs are capable of performing their vital function as specialized projection neurons, mainly from the aspect of their energetics. We have structured this paper to initially describe the features of high functional activity and high energy demands of the RGCs, illustrate distinct non-homogeneous nature of energy distribution and consumption within RGC, and their unusual oxidative metabolism properties when compared with the inner segments of the photoreceptors where a high density of mitochondria are accumulated. To understand how RGCs respond to physiological and pathological challenges, the concept of the compartmentation has been utilised. However, each compartment has to be perfectly and precisely integrated structurally and functionally. The roles of mitochondria, axonal transport, axonal cytoskeleton proteins have been emphasized using an elevated IOP and ischemic model. Finally, glaucoma is used as an example to describe the importance of RGCs energetics.
Section snippets
Non-homogeneous energy distribution and consumption in RGCs
Whether or not energy distribution is homogeneous in the cytoplasm of a living cell remains an interesting question. Before discussing energy distribution and consumption in RGCs, we would like to provide a brief overview of this concept with reference to most living cells. The principle of non-homogeneous, intracellular energy distribution and consumption has been generally accepted. ATP molecules exist mostly in a structure-associated form (Friedrich, 1985, Kellermayer et al., 1986) and have
The concept of microcompartmentation
The concept of “microcompartmentation” was introduced in 1985 (Friedrich, 1985) following the observation of restricted molecular mobility inside living cells. Since then, a large body of accumulated evidence have supported the existence of microcompartmentation and have explored the functional significance of this model (Bereiter-Hahn and Vöth, 1994, Clegg, 1984, Clegg, 1988, Jones and Aw, 1988, Kellermayer et al., 1986, Minaschek et al., 1992, Wang et al., 2012, Whitmore et al., 2005).
RGC compartmentation
The retina has been described as a window to the brain (London et al., 2013). The optic nerve has the same organization as the white matter of the brain, particularly when the constitution of glia and the organisation of vasculature in the two structures are compared. RGC bodies are located in the RGC layer which has an average thickness between 10 and 20 μm in the nasal retina and 60–80 μm in the macular region. RGCs may be arranged as a single row in the peripheral retina and may be up to 10
Importance of axonal transport
As mentioned previously, the axon has very little protein-synthesising capability. Its viability therefore depends on the timely delivery of material synthesised in the cell body. Movement of protein and organelles between cell compartments is predominantly achieved by axonal transport which is a bidirectional, energy-dependent process. Examples of cargo mobilised by axonal transport include mitochondria, cytoplasmic vesicles, neurotrophic factors and cytoskeleton proteins. Unlike the vascular
Energetics of RGCs and glaucoma
In this review we have described the division of the retinal ganglion cell into distinct compartments. We have provided a rationale for this division and have given an in-depth summary of the unique metabolic, structural, extracellular and functional requirements of each compartment. We have also described the role of vital functional processes, such as axonal transport, and supporting cells, such as astrocytes, in RGC health. Finally, we have documented (largely using data from our own
Conclusions
The unique configuration of the RGC reflects the functional activity of individual subcellular compartments. The dendrite, cell body, non-myelinated axon and myelinated axon compartments exist in dramatically different extracellular environments and have specific energy requirements. Energy demands are closely coupled with functional activity and RGC energy homeostasis is therefore dependent upon a complex control system that mobilises mitochondria and energy substrates to satisfy regional
Acknowledgements
Grant support was provided by the National Health and Medical Research Council of Australia and the Australian Research Council Centre of Excellence in Vision Science. Expert technical assistance was provided by Mr Dean Darcey.
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Percentage of work contributed by each author in the production of the manuscript is as follows: Dao-Yi Yu, 60%; Stephen J Cringle, 15%; Chandrakumar Balaratnasingam, 10%; William H Morgan, 5%; Paula K Yu, 5%; Er-Ning Su, 5%.