Ординатура / Офтальмология / Английские материалы / Biochemistry of the Eye 2nd edition_Whikehart_2003

240 • Biochemistry of the Eye

Figure 8–11

Basic anatomical and neurochemical properties of ocular autonomic nerves.

These nerves also supply innervation for tear production (especially the parasympathetic division) and eyelid tension. Note the difference in neurotransmitters and receptors in the terminal nerves of each division.

Figure 8–12

Schematic outline of the principal neurons of the retina. Although most neurons are connected by classical synaptic junctions using neurotransmitters, some make use of direct chemical ion transfer by use of gap junctions (not shown). These junctions include rod-to- rod, rod-to-cone and cone-to-cone connections. Also not shown here are interplexiform cells and the glial cells of Müller. The former transfer signals from amacrine cells to horizontal cells. The latter act as cell insulators, retina boundaries, and maintenance cells for the photoreceptors. See text for other cell functions.

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domains are considered responsible for actual binding to the presynaptic vesicles in an undetermined manner. An active zone, at the bottom of the ribbon adjacent to the cleft membrane (not shown in the figure) is the location where vesicle fusion with the membrane takes place. In fact, many different proteins are known to be involved in both the function of the ribbon synapse and the presynaptic membrane itself (Morgans, 2000). As with other synapses, calcium channels facilitate the process of vesicle fusion and neurotransmitter release. However, the channels are not the typical channels found in conventional synapses and may not represent a channel type found in any other part of the nervous system (Taylor, Morgans, 1998). The function of these channels is to induce a partial decrease in the release of glutamate with light. That is, they slow the ribbon fusion device described above.

The most direct route of a light signal passing through the retina (on-center mechanism) would proceed from a cone photoreceptor onto a bipolar cell and then onto a ganglion cell. From the ganglion cell, the signal leaves the retina and proceeds to the lateral geniculate nucleus where nerves (optic radiation fibers) depart that nucleus and send their processes to the primary visual cortex of area 17. Such a pathway, here limited to just the retina, is shown in Figure 8–14. The pathway proceeds from the cone photoreceptor via synapse 1 (all synapses are circled) to bipolar cell 1a and on to the ganglion cell by way of synapse 2. The neurotransmitter of synapse 1 (and of all rod and cone photoreceptors) is glutamate (glutamic acid) (Masland, 2001). In the dark, or in darkadapted conditions, both photoreceptor types continuously release their neurotransmitters to receptors located on bipolar cells. As previously mentioned, this is rather unusual since nerve presynapses generally release little or no neurotransmitter when inactive. This situation is the direct result of the continuous flow of Na+ ions into photoreceptor outer segments and is referred to as the “dark current” (refer to Figure 6–10A and B). When the Na+ ion flow is interrupted by light transduction, the resulting hyperpolarization (i.e., build-up of net negative charge) in the photoreceptor decreases the release of glutamate by opening the Ca+2 ion channels mentioned. Note that this role of Ca+2 ions at the synapse

Figure 8–14

Principal cells and synapses involved in cone center on and off light reception.

Area outlined in gray. The signals are sent in sequence to the blackened cells as described in the text.

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should not be confused with the multiple roles that Ca+2 has in the outer segments (see Chapter 6)

The resulting decrease in glutamate release causes cation channel receptor proteins for Na+ to open indirecty in the bipolar postsynaptic membrane via a cGMP channel protein. This, in turn, allows the release of bipolar cell neurotransmitters to ganglion cell receptors at synapse 2 (Kandel, Schwartz, Jessell, 2000). The specific neurotransmitter in all bipolar cells is also Glu and is not released when the cell is not stimulated contrary to the condition for photoreceptors (Euler, Masland, 2000).

The off signal mechanism is a second direct route that occurs when light is turned off or suddenly decreased. It proceeds by synapse 1 to bipolar cell 1b (see Figure 8–14). When light is present, the receptor maintains closed channel proteins for Na+ (see Figures 6–9 and 6–10). As a result of this, the bipolar cell hyperpolarizes and decreases its release of glutamate to its ganglion cell at synapse 3 just as a photoreceptor would do in the presence of light. When light is turned down or turned off, the release of Glu from the cone presynapse, opens Na+ channels directly in the postsynaptic membrane that, in turn, depolarizes the bipolar cell and causing it to release Glu tonically (temporarily) in its synapse with its ganglion cell. This action activates the appropriate ganglion cell (3 in the figure) just as depolarization of a bipolar cell occurred with the on center mechanism. The mechanisms and neurotransmitters involved are summarized in Figure 8–14 and Figure 8–15.

An indirect deactivation mechanism also exists and involves partial inhibition of activated ganglion cells that are controlled by a so-called “surround” physiology. This includes light signals received by neighbor cone photoreceptors. One purpose of an indirect mechanism is for the operation of visual acuity; that is, the ability to distinguish borders or edges of a visualized object. In Figure 8–16, when a greater amount of light is obtained by an adjacent (or surround) cone photoreceptor, the synapse from that cone photoreceptor sends the signal in two directions. The most direct route is to bipolar cell 2a as usual. There the signal will produce the same action as the cone photoreceptor in Figure 8–14 using the same neurotransmitters and receptors. In addition, the inhibition of glutamate release from a surround cone photoreceptor (i.e., the neighbor with the stronger light signal) activates a horizontal cell that will release GABA as a neurotransmitter onto a center cone photoreceptor (the one having weaker light reception at synapse 2). The receptor protein for GABA (whose characteristics are unknown) then allows a continued release of glutamate from the center cone photoreceptor (as though a normal dark current existed) and, therefore, prevents release of neurotransmitter from the bipolar cell 1a at synapse 3 (on). In other words, it maintains an off signal in the center on ganglion cell (Ehinger, Dowling, 1987; Berson, 1992; and Kandel, Schwartz, Jessell, 2000). What is “center” and what is “surround” is relative to the strength of the light signals received by adjacent photoreceptors.

Rod photoreceptors, whose physiology is more concerned with detection of low levels of light, are indirectly connected to ganglion cells by way of amacrine cell synapses. This is shown in Figure 8–17. This is an indirect pathway, in which rod photoreceptors piggyback on to cone bipolar cells. It suggests that rod photoreceptors are a more recent evolutionary development of the retina (Masland, 2001). The sequence of connections is: rod photoreceptor → rod bipolar cell (synapse 1) using glutamate as a neurotransmitter; rod bipolar cell → amacrine cell (synapse 2) using glutamate as a neurotransmitter; amacrine cell → cone bipolar cell (on synapse 3)

244 • Biochemistry of the Eye

Figure 8–15

Biochemical and physiological diagram of neurotransmission differences between “on” and “off” mechanisms when light is turned on or off. Note, in particular, how the release (light off) of Glu affects the two classes of bipolar cells differently and, likewise, how the nonrelease (or decreased release) of Glu differentially affects the two classes of bipolar cells. This is largely due to whether the Na+ channel protein is present as a NT receptor for Glu or whether the channel protein function is mediated by cGMP binding (i.e., phosphodiesterase, PDE, functions as a receptor for Glu).

Figure 8–16

Principal cells and synapses involved in cone surround “on” light reception.

Area outline in gray. Signals are sent by two pathways (blackened cells) in which the pathway via the horizontal cell will inhibit the signal from an adjacent photoreceptor. See text for explanation of biochemistry and physiology.

possibly using indoleamine as a neurotransmitter (see Ehinger, Dowling, 1987) and, finally, cone bipolar cell → ganglion cell (synapse 4) using glutamate as a neurotransmitter. All of these pathways, transmitters, and receptors are summarized in Table 8–3.

Ocular Neurochemistry • 245

Figure 8–17

Principal cells and synapses involved in rod light reception. Area outlined in gray. Signals sent through blackened cells. It is important to note that there is no direct connection of rod bipolar cells to ganglion cells. See text for explanation and description of neurotransmitters involved.

T A B L E 8 – 3 SOME BIOCHEMICAL SYNAPTIC PATHWAYS OF THE RETINA

1This is the indirect pathway to the adjacent cone photoreceptor.

2This is the direct pathway to the ganglion cell that is equivalent to the center ON type shown above.

Ocular Neurochemical Pathology

In general, neurotransmission in the eye functions quite efficiently except when disrupted by degenerative conditions (such as retinitis pigmentosa) or by nerve lesions outside of the eye (such as Horners syndrome). Parkinsons disease has also been found to affect the visual system at both the level of the brain and the retina (Hunt, Sadun, Bassi, 1995). In the retina, Harnois and DiPaola (1990) have found a correlation with retina levels of dopamine and visual disturbances of patients with Parkinsons disease. These patients lose some contrast-sensitivity ability that, among other things, decreases their ability to read. Compared to normal individuals with an average retina concentration of 1ng dopamine per mg of protein, untreated Parkinsonian patients were found to have levels of

246 • Biochemistry of the Eye

approximately 0.52 ng dopamine per mg of protein. Dopamine is a neurotransmitter found in some amacrine cells. Although its function was not described in any previous discussion in this text, evidence indicates that amacrine cells (some of which use dopamine) serve as intermediate cells for the lateral transfer of signals across the retina. In short, they appear to be part of an auxiliary system for visual acuity. Still another retina cell type, known as an interplexiform cell, may also use dopamine and have a similar function (Ehinger, Dowling, 1987; Vigh, Banvolgyi, Wilhelm, 2000). Moreover, recent studies, as explained by Nguyen-Legros, Versaux-Botteri, Vernier (1999), suggest that receptors for dopamine (D1 and D2 proteins) are widespread throughout all retinal cells. The implications of this in respect to retinal function have yet to be fully understood. However, it implies that dopamine may diffuse and cause effects beyond the confines of synaptic clefts. Therefore, the role of this neurotransmitter may also include neuromodulator functions. This is a role previously unsuspected and one that may be quite subtle in visual functions.

S U M M A R Y ● Neural transmission occurs with the depolarization of nerve plasma membranes. The transmission results with the entry of Na+ ions into the

neuron and ceases with the sequential loss of K+ ions to the outside of the

nerve. This activity is facilitated by cation-gated, channel proteins and is

initiated by an incipient, vicinal depolarization. In myelinated nerves, ion

movement is limited to nerve nodes such that ion movement causes depo-

larization to leap from node to node. This causes the transmission rate to

increase greatly. At nerve synapses, depolarization is converted to the

release of neurotransmitters that diffuse across a small space (cleft) to

bind to receptor proteins. This produces either a depolarization or a

hyperpolarization in the postsynaptic cell and imitates, in some cells, a

hormone mechanism in which G proteins are intermediates producing a

physiological response. There are four classes of neurotransmitters:

acetylcholine, catecholamines, amino acids, and amino acid derivatives.

Of these, acetylcholine and norepinephrine have been very well described.

Acetylcholinesterase is used to degrade acetylcholine in the synapse and

inhibitors of this esterase have been used as therapeutic agents to

prolong the concentration of acetylcholine in synapses where they occur.

In the eye, the inhibitors have been used to control glaucoma and to

restore normal pupil size after an eye examination. The two ocular auto-

nomic nervous systems use acetylcholine as a neurotransmitter at their

ganglia. Nicotinic acetylcholine receptors are present there and produce

a “fast” response. In the ocular parasympathetic division of postgan-

glionic nerves, acetylcholine is also the neurotransmitter, but a “slower”

acting muscarinic receptor protein is found on the muscle receptor mem-

branes. These receptors use G proteins. In the ocular sympathetic divi-

sion of postganglionic nerves, norepinephrine is the neurotransmitter.

Ocular Neurochemistry • 247

There are nine kinds of receptor proteins present: six α-classes and three

β-classes. All are “slow” acting and make use of G proteins.

In the retina, a variety of neurotransmitters may be found. However, photoreceptor cells that use glutamate possess an unusual mechanism by which they transmit signals. These cells normally release glutamate when they are inactive. When they detect light, they hyperpolarize and decrease their release of glutamate. Their postsynaptic cells are either hyperpolarized themselves or depolarized depending on their receptor mechanisms. There are several mechanisms by which the retina responds to light and brings about a cascade of neurotransmission in amplified, inhibited or modulated fashions: cone on/off, cone center/surround, and rod dominated. Each system uses a specific sequence of neurotransmitters and receptors through a variety of cells. Dopamine has been found to function in the retina as both a neurotransmitter and a neuromodulator. Its levels are decreased in Parkinson’s disease and this has been linked to losses of visual acuity.

P R O B L E M S ● 1. What is the location of the Na+ ions that trigger the opening of the cation channel protein (as pictured in Figure 8–3)? Explain your answer.

2.Both norepinephrine (produced as a neurotransmitter in the iris) and epinephrine (produced as a neurohormone in the adrenal medulla and released into the circulation) will increase the diameter of the pupil by stimulating the dilator muscle of the iris. The process is called mydriasis. Phenylephrine is a chemical analogue of epinephrine and is used as a topical agent on the cornea to produce mydriasis for ocular examinations. Unlike norepinephrine, the effect of phenylephrine lasts for several hours. Why might this occur?

3.If the gene for the RIBEYE protein, present in ribbon synapses, were defective, what might be the biochemical effect produced at the pedicles of cone photoreceptors? In the same case, what might be the physiological effect on the visual system?

4.When a light is turned off in a room, why is glutamate released from the off center bipolar cells to the off center ganglion cells? What effect does the release of glutamate have on the ganglion cells?

5.What retina effects occur to dopamine in Parkinsons disease? How is overall vision affected?

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