Bipolar Cell Pathways in the Vertebrate Retina by Ralph …

Ralph Nelson and Victoria Connaughton

1. Introduction.

Retinal ganglion cells are typically only two synapses distant from retinal photoreceptors, yet ganglion cell responses are far more diverse than those of photoreceptors. The most direct pathway from photoreceptors to ganglion cells is through retinal bipolar cells. Thus, it is of great interest to understand how bipolar cells transform visual signals.

Werblin and Dowling (1) were among the first to investigate light-evoked responses of retinal bipolar cells. Based on these studies using penetrating microelectrodes, they proposed that retinal bipolar cells lacked impulse activity, and that they processed visual signals through integration of analogue signals, that is synaptic currents and non-spike-generating voltage-gated membrane currents.

Frank Werblin and John Dowling discovered the ON or OFF light-evoked physiology of retinal bipolar cells (1). They characterized these neurons as processors of analogue visual signals that did not use impulse generation. The work was done at Johns Hopkins University as a part of Frank Werblins doctoral dissertation under John Dowlings mentorship.

Werblin and Dowing also proposed that retinal bipolar cells come in two fundamental varieties: ON-center and OFF-center (Fig. 1). Both types displayed a surround region in their receptive field that opposed the center, similar to the classic, antagonistic center-surround organization earlier described for ganglion-cell receptive fields (2). Ganglion cell receptive field organization is further reviewed in the Webvision chapter on ganglion cells. ON-center bipolar cells are depolarized by small spot stimuli positioned in the receptive field center. OFF-center bipolar cells are hyperpolarized by the same stimuli. Both types are repolarized by light stimulation of the peripheral receptive field outside the center (Fig. 1). Bipolar cells with ON-OFF responses were not encountered (1). ON-OFF responses, excitation at both stimulus onset and offset, first occur among amacrine cells, neurons postsynaptic to bipolar cells.

The Werblin and Dowling characterization of bipolar-cell physiology has proved quite durable over many decades. The notion that bipolar cells do not spike has found exception for some bipolar types. Dark-adapted Mb1 (rod bipolar cells) of goldfish generate light-evoked calcium spikes. These spikes originate in bipolar-cell axon terminals (3, 4). Through genetic imaging techniques this finding has been extended to the axon terminals of many zebrafish bipolar-cell types. In these studies bipolar terminals were labeled transgenically with the Ca2+ reporter protein SyGCaMP2 and light-induced fluctuations in Ca2+ were followed by 2-photon photometry. Fully 65% of the terminals delivered a spiking Ca2+ signal (4). In the cb5b bipolar-cell type of ground squirrel retina Na+ action potentials are driven by light. Other bipolar types in this retina do not exhibit spiking (5). These results suggest that bipolar cells are responsible for significantly more of the encoding of visual signals than had been previously supposed, and that axon-terminal spiking is actively involved. Impulse generation in bipolar cells is further discussed in the section on Voltage-gated currents.

Figure 1. Retinal bipolar cells initiate ON and OFF pathways. Microelectrode recordings of voltage responses from mudpuppy retinal neurons reveal two sorts of retinal bipolar cells: those hyperpolarized by central illumination (OFF Bipolar Cell) and those depolarized by central illumination (ON Bipolar Cell). In each case membrane potential is restored by concomitant illumination of annular rings surrounding the center. Such responses are typically 10 mV in amplitude and lack impulse activity. The absolute response latency to the light step above is about 100 msec for these suprathreshold stimuli. The illustration is taken from Werblin and Dowling, 1969 (1).

Morphology and connectivity

Anatomical investigations of bipolar cells reveal a multiplicity (4-22 depending on species) of different morphological types (6-12), significantly more than the just two types that early physiology implied. The diversity of human retinal bipolar types is illustrated in Fig. 2. Nonetheless all of these are either ON- or OFF-types and their diversity results from other factors, such as differing connectivity with photoreceptors and differing postsynaptic targets, as evidenced in the diversity of dendritic and axon-terminal ramification patterns. Some bipolar cells are postsynaptic only to rods, others only to cones (Fig. 2), and still others receive mixed rod-cone input. Among cone-selective bipolar cells, some innervate only red, green, or blue cones, while others are diffuse, that is, not selective (13-19). Different bipolar types express different glutamate receptors at subsynaptic contacts with cones.

Bipolar cell axon terminals are either mono- or multistratified, depending on the location of axonal boutons and branches in the inner plexiform layer (IPL). Differing terminal position and branching morphology within the IPL suggests that different morphological types selectively innervate different types of amacrine and ganglion cell (Fig 2).In primate retinas, bipolar cells are described as diffuse or midget types, based on the extent of the dendritic arbor. Midgets contact only a single cone, while diffuse types contact multiple cones. Bipolar cells are also termed flat or invaginating (20) depending on the placement of dendritic tips, either on the surface of (flat), or penetrating within photoreceptor synaptic terminals to approach presynaptic ribbons (invaginating).Fig. 2 illustrates 11 morphological types of bipolar cell seen in Golgi-stained human retinas.

Figure 2. Dendritic and axonal stratification patterns of bipolar cell types in human retina. The illustration is courtesy of Helga Kolb.

Bipolar cell axon terminals are either mono- or multistratified, depending on the location of axonal boutons and branches in the inner plexiform layer (IPL). Differing terminal position and branching morphology within the IPL suggests that different morphological types selectively innervate different types of amacrine and ganglion cell (Fig 2).In primate retinas, bipolar cells are described as diffuse or midget types, based on the extent of the dendritic arbor. Midgets contact only a single cone, while diffuse types contact multiple cones. Bipolar cells are also termed flat or invaginating (20) depending on the placement of dendritic tips, either on the surface of (flat), or penetrating within photoreceptor synaptic terminals to approach presynaptic ribbons (invaginating).Fig. 2 illustrates 11 morphological types of bipolar cell seen in Golgi-stained human retinas.

2. Different glutamate receptor types for ON and OFF bipolar cells.

Light responses in bipolar cells are initiated by synapses with photoreceptors. Photoreceptors release only one neurotransmitter, glutamate (21); yet bipolar cells react to this stimulus with two different responses, ON-center (glutamate hyperpolarization) and OFF-center (glutamate depolarization). Different postsynaptic glutamate receptor proteins mediate these different membrane polarizing mechanisms. The different glutamate-gated responses are associated with the differential expression of either ionotropic (iGluR) glutamate receptors (OFF bipolar cells), metabotropic (mGluR) glutamate receptor types (ON bipolar cells) or glutamate transporters (ON bipolar cells). As a result, signal transduction at the photoreceptor-to-bipolar synapse has a range of properties. The process of splitting images into multiple components tuned to selective visual features begins with differentiation of different photoreceptor types but is then greatly elaborated at the synapses between photoreceptors and bipolar cells.

Metabotropic responses of ON bipolar cells: mGluR6, Go, TRPM1, Nyctalopin

The conductance of ON bipolar cells increases in the light, whereas OFF bipolar cell conductance decreases (22, 23). The decrease in OFF bipolar cell conductance is easily explained as a loss of excitation by glutamate, as light inhibits glutamate release from photoreceptors (24). The positive reversal potential of the ON bipolar cell light response, coupled with a conductance increase (22, 25), implies that glutamate blocks a cation-permeable channel. Originally a puzzle, this was the first evidence of what we now understand as the action of metabotropic glutamate receptors (mGluRs). These receptors do not form ion channels themselves, but act as isolated antennae on the cell surface sensing glutamate and activating intracellular pathways, ultimately affecting membrane potential through mechanisms several steps removed from the binding site for glutamate. Metabotropic receptors have been identified on the axon terminals of both photoreceptors (26) and bipolar cells (27) where they serve as autoreceptors regulating glutamate release. However, the expression of one specific mGluR in the subsynaptic membrane of ON bipolar cell dendrites, the APB receptor, is unique to retina, where it is used in the direct signal transmission pathway from photoreceptors to ON bipolar cells.

Figure 3. Metabotropic glutamate receptors in the ON pathway. The glutamate agonist 2-Amino-4-Phosphonobutric acid (APB, later termed DL-AP4) interferes with light responses and membrane physiology of ON-center bipolar cells in mudpuppy. A. APB abolishes light responses (the rectangular depolarizing events), hyperpolarizes the membrane potential, and increases the membrane resistance. The latter is measured by the amplitude of voltage responses to injected current pulses (arrow). B. 3 mM cobalt, a blocker for synaptic release of glutamate from photoreceptors, abolishes light responses in an ON bipolar cell and depolarizes the membrane potential. The membrane potential can be later restored by application of APB, which acts as a substitute for the missing photoreceptor glutamate. As APB is selective for a subset of metabotropic glutamate receptors, synaptic transmission of light responses to ON bipolar cells must rely on a metabotropic mechanism. The illustration is adapted from Slaughter and Miller, 1981 (28).

The mGluR6 receptor

Slaughter and Miller (28) were the first to observe that the metabotropic glutamate agonist 2-amino-4-phosphonobutric acid (APB or DL-AP4, with the L enantiomer being effective) completely blocks the light responses of ON bipolar cells. In these neurons, APB acts as a substitute for photoreceptor-released glutamate (Fig. 3AB). Thus, ON bipolar cells utilize a metabotropic pathway to sense light-induced variations in release of photoreceptor glutamate. The metabotropic receptor has been identified as mGluR6 (29, 30). Transgenic knockout mice lacking the mGluR6 gene lack the electroretinographic b-wave (Fig. 4AB), an evoked-potential component associated with ON bipolar activity (31). The relation of electroretinogram components to cellular electrophysiology is further discussed in the Webvision chapter The Electroretinogram: ERG. Immunocytochemical localization for mGluR6 shows staining in the invaginating dendritic tips of monkey bipolar cells (Fig. 5) (32). Invaginating bipolar cells are thought to be mainly ON types in primate retina. Some foveal flat contacts also stained for mGluR6 (32).

Figure 4. MGluR6 is the metabotropic glutamate receptor expressed by ON bipolar cells. Light evoked ERG responses from the eye of a wild type (A, +/+) and a mutant (B, -/-) mouse deficient in the gene encoding mGluR6. The b-wave, which originates from the light responses of ON bipolar cells is absent in the mutant mouse. The illustration is adapted from Masu et al, 1995 (31).

Figure 5. Immunostaining for the metabotropic glutamate receptor mGluR6 selectively labels dendritic tips of invaginating bipolar cells (ib) in monkey retina. The adjacent dendritic contacts from horizontal cells (h) and the flat contact (f) from a flat cone bipolar cell are not labeled, nor is the presynaptic cone pedicle (c).The illustration is from Vardi et al., 1998 (33).

The G-protein Go

In addition to mGluR6, the G-protein Go is cytoplasmically localized in the dendritic tips of ON bipolar cells (Fig. 6) (33). Removal of the alpha subunit (Go) by knockout results in b-wave loss (34), similar to the mGluR6 knockout. Go was originally localized in rod bipolar cells, known to be ON-type, in a screen of potential G-protein second messengers for the metabotropic light response (35). This suggests that Go is directly involved in the intracellular pathway following mGluR6 activation.

The ion channel coupled to the APB receptor was originally thought to be cGMP-modulated (36).The closure of ion channels following APB binding onto mGluR6 seemed to require GTP and phosphodiesterase similar to phototransduction (36). However, the exact cascade by which this happened was less clear, as blocking phosphodiesterase (PDE) activity, or adding non-hydrolyzable cGMP analogs, did not inhibit the glutamate responses generated through APB-receptors (37). Further, it was Go that suppressed glutamate-gated current in ON bipolar cells, not transducin, the G-protein of the phototransduction cascade (37). Thus, removal of cGMP appears not to be required for channel closure (37).

Figure 6. Immunostaining for Go, the the alpha subunit of the G-protein Go, localizes to the invaginating dendritic tips of a rod bipolar cell (left) and a cone bipolar cell (right) in cat retina. Go is required for light activation of ON bipolar cells. The illustration is from Vardi, 1998 (33).

The TRPM1 channel

In agreement with these findings, recent work suggests the ON-bipolar-cell ion channel downstream of the mGluR6 receptor is not cGMP-gated (38). Rather, this non-selective cation channel identified as a TRPM1-L channel appears to be regulated by Go (38-40) in conjunction with G (41). The activity of the TRPM1 channel requires the presence of mGluR6, as the channel, though present, can not be activated in mGluR6 knockout mice (42).

TRP channels, or transient receptor potential channels, first identified in Drosophila photoreceptors (43), are present in all animal groups, including vertebrates (44), and as many as 28 channel subtypes have been identified. The TRP superfamily includes 7 subfamilies separated into two groups: TRPC, TRPV, TRPM, TRPN, and TRPA channels form Group 1; TRPP and TRPML channels form Group 2. TRPM1-L or melastatin, a melanoma related TRP channel, belongs to Group 1, and is found in ON bipolar cells. All channels share structural similarities and are permeable to cations; however, there is great functional diversity among the different channel subtypes. TRP channels are involved in many sensory systems including vision, hearing, taste, temperature-sensitivity, and osmoregulation, and are also involved in human disease (44-48).

Figure 7. TRPM1 channel knockouts lack photoresponses in ON-bipolar cells. A. In a wild type mouse, antibody staining for TRPM1 reveals localization in bipolar cells. No antibody staining is evident in the knockout. B. ON-bipolar-cell patch recordings in wild type mice reveal inward currents in response to light stimulation. This is the normal response of an ON-type bipolar cell as these cells are excited by light. No inward currents occur in ON-bipolar-cell recordings from the knockout. The illustrations are from Koike et al, 2010 (38).

In retina, TRP channels have been identified on photoreceptors (49), amacrine cells (50, 51), and ON-type bipolar cells. ON-bipolars (Fig. 7A), specifically, are antigenic for TRPM1 channels (52, 53) or TRPM1-L (38, 39, 54). Immunocytochemical and/orin situhybridization studies have localized TRPM1 expression to the dendritic tips of ON-bipolar cells (38, 39, 52), though labeling is seen in cell bodies and axons as well (Fig. 7A). TRP channels are absent in OFF-type bipolar cells. TRPM1-L channel currents have a reversal potential ~0mV (38) similar to the reversal potential of glutamate-gated currents in these cells. TRPM1-L has been shown to co-localize with and/or be functionally coupled to mGluR6 (38, 40, 42, 52). In transfected CHO cells that express mGluR6, Go, and TRPM1-L, Koike and colleagues (38) showed that all three of these components must be present for glutamate-evoked whole-cell currents to be recorded. Cells expressing only mGluR6 and Go,or only Goand TRPM1-L, did not respond to glutamate application (38, 39). These findings suggest TRPM1 channels are downstream of the mGluR6 receptor and are necessary for glutamate-elicited responses in these cells. Further, TRPM1 -/- knockout mice (Fig. 7B) do not have light-evoked ON-bipolar-cell responses and there is no ERG b-wave (38, 39, 55). The loss of response is similar to that reported for mGluR6 -/- mice (Fig. 4) (31, 56), again suggesting that both mGluR6 and TRPM1 channels are required for ON-bipolar-cell photic responses. While all cone bipolar cells in mouse appear to use an mGluR6 synapse with cones, there is evidence that some of these cells may modulate a cation channel in addition to TRPM1-L. In the TRPM1 -/- mouse, the mGluR6 antagonist CPPG still blocks a minor APB-induced membrane current (52).

Figure 8a. The insertion of the fusion protein EYFP-nyctalopin into nob NYX -/- mice re-establishes nyctalpin expression. Expression can be localized with EYFP antibodies. A. DIC image of mouse retinal slice. OS, outer segments; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GC, ganglion cell layer. B. Wild type mouse is not labeled by anti-GFP. C. EYFP-NYX rescue mouse shows fusion protein localization in bipolar-cell dendritic tips within the OPL. D. High magnification of C. E. peanut agglutinin reaction labels cone terminals. F. Overlay of D and E shows NYX expression (nyctalpin) is localized in cone terminals (yellow). Green localization is presumed in rod terminals. Scale bar in A, B and C is 50 m. The illustration is from Gregg et al, 2007 (57).

The proteoglycan nyctalopin

Nyctalopin is another protein expressed on the dendritic tips of ON-bipolar cells (Fig. 8a). It is encoded by the NYX gene. NYX is required for light- and glutamate-elicited responses in ON bipolar cells (57). Mutant nob mice (58) lack an ERG b-wave and are not responsive to focal applications of glutamate onto the bipolar cell dendritic arbor (57). In wild type mice ON bipolar cells respond with outward currents to this treatment, but in nob mice they do not (Fig. 9). The nob strain is an NYX -/- mutant (59). Generation of transgenic nob mice selectively expressing EYFP-nyctalopin fusion protein in bipolar cells completely rescued the mutant phenotype. Cellular expression was restricted to bipolar cells using a regulatory sequence for GABAc1, a GABA receptor subunit selectively produced by bipolar cells. In the EYFP-NYX line, the fusion protein expression was localized to the tips of ON-bipolar cells (Fig. 8a), the b-wave was restored, and inner retinal function was similar to controls (57).

Figure 8b. Morphology of zebrafish retinal neurons expressing nyctalopin. The transgenic strain contains an MYFP gene driven by the regulatory sequence for NYX (nyctalopin). A-D retinas from 3-day post fertilization (3 dpf) larvae show only bipolar cells, with a broad distribution of axonal filopodia within the inner plexiform layer (IPL). E-G. By 6 dpf the filopdial pattern of bipolar cell axons is restricted to the inner half of the IPL, a characteristic of ON bipolar morphology. The illustration is from Schroeter, Wong and Gregg, 2006 (60).

In zebrafish a membrane-targeted yellow fluorescent protein (MYFP) reporter strain has been generated using the upstream regulatory sequences for the NYX gene to express MYFP. This reporter marks a subset of ON-type bipolar cells with characteristic long axons and terminal boutons restricted to the inner half of the inner plexiform layer. Many of these also express the ON-bipolar marker protein kinase C (PKC) (60). This genetic reporter shows the complete morphology of the cells expressing the nyctalopin gene. This transgenic tool was used to follow embryonic refinement and development of axonal projection patterns for nyctalopin-expressing ON bipolars (60) (Fig. 8b).

Subsequent studies have reported that nyctalopin complexes with both mGluR6 and TRPM1 channels in ON-bipolar cells, serving a structural role that allows proper assembly and organization of the receptor and the channel (61). In addition, nyctalopin is able to modulate TRPM1 channels, as is mGluR6 (42, 62). Thus, glutamate binding onto mGluR6 activates a G-protein (Go and/or G) leading to the closure of TRPM1 channels. The receptor and the channel are held in close proximity by nyctalopin. Alteration or mutation of any of these components mGluR6, nyctalopin, TRPM1, and/or Go can lead to a loss of response by ON-bipolar cells. In agreement with this, individuals with congenital stationary night blindness (CSNB discussed below) display a loss of ON-bipolar cell responses as evidenced in an absent ERG b-wave, and mutations in the genes encoding mGluR6, nyctalpin, and TRPM1 are associated with at least 75% of CSNB cases (62).

Figure 9. Bipolar-cell glutamate responses in the nob (nyctalopin) knockout mouse. Patch recordings of glutamate-responses reveal outward, metobotropic glutamate, currents in both rod bipolar cells and ON-type cone bipolar cells (DBC) in control mice. No glutamate currents are recorded for these cell types in nob mice. OFF cone bipolar cells (HBC) respond with inward AMPA/kainate currents in both control and nob mice. The holding potential was -60 mV. Glutamate puffs are 100 msec from pipettes filled with 1-5mM glutamate. The illustration is from Gregg et al, 2007 (57).

Modulators and subtypes

Calcium ions are a modulator of the ON bipolar metabotropic ion channel. Calcium ions, entering through the TRPM1 ion channel (63, 64) affect channel function, either by directly down regulating the channel (63) or by activating calcium-dependent enzymes, such as CaMKII (65-67), which modulate ion channel conductance. cGMP has been shown to selectively enhance ON bipolar cell responses to dim light, and may play a modulatory role for the TRPM1 channel (68).

Metabotropic receptors for ON-center bipolar cells have sustained and transient subtypes (69). The molecular basis is not yet known. However, it appears that the sustained and transient responses of ON-center ganglion cells, such as the classic X- and Y-types (70), may have their origin, at least in part, in the type of glutamate receptor expressed on the bipolar cells which innervate them (71).

Glutamate transporter mediated responses of ON bipolar cells

Ionotropic glutamate receptors with transporter-like properties are also present on some ON-center bipolar-cell dendrites. When photoreceptor glutamate binds to these transporters, a Cl conductance forms and hyperpolarizes the cells in the dark (Fig. 10). Release from this Cl inhibition occurs in the light with the decrease in glutamate released from photoreceptors. This allows the bipolar cells to depolarize (Fig. 10). Like transporters, this glutamate-gated Cl mechanism requires [Na+]o in order to function. Thus far this mechanism has been found as a dendritic glutamate receptor only in cyprinid ON bipolar cells (72-74), though it is reported in turtle, salamander and mouse photoreceptors (75-78) and is also present in mammalian central nervous system (79). Interestingly it occurs on the axon terminals of mouse rod and cone bipolar cells, where it acts to regulate glutamate release through inhibitory feedback (78).

Figure 10. An alternate ON-bipolar synaptic mechanism is a glutamate-activated-chloride channel. Puffs of glutamate mimic photoreceptor dark release in patch recordings from bipolar cells in a zebrafish retinal slice. A. Glutamate-evoked currents are outwards for physiological ranges of membrane potential, which are positive to ECl (Cl reversal potential). They are inwards at more negative potentials. The results are consistent with an ON-center mechanism driven by changes in Cl conductance. B. The 63 mV reversal potential is consistent with a model where photoreceptor glutamate opens Cl channels. Glutamate gated Cl currents are called Iglu (73) and result from the binding of glutamate to excitatory amino acid (EAAT) transporters. The illustration is from Connaughton and Nelson, 2000 (72).

Some non-mammalian bipolar cells contain both the APB and the ionotropic (transporter-like) receptor on their dendrites, while other ON-cells express either the metabotropic or the ionotropic receptor but not both (72, 73). EAAT5 has been identified as the chloride-channel-forming glutamate transporter (80). The ionotropic mechanism is used for sustained transmission between cones and bipolar cells (81, 82), and is likely to be a fast mechanism as compared to metabotropic pathways, which involve multi-step intracellular pathways and are often relatively slow (22).

The classic Mb rod bipolar cell of fish makes synapses with both rods and cones. The rod synapse mediates a conductance increase with reversal potential positive to resting potential. The cone synapse mediates a conductance decrease with reversal potential negative to the resting potential (82). Both mechanisms provide ON-type photic responses. In retrospect it would appear that the rod synapse is metabotropic, while the cone synapse is transporter-like, two different, selectively directed post-synaptic glutamate mechanisms on the same neuron.

AMPA kainate receptor expression in ON bipolar cells

ON-center bipolar cells of mammals are immunoreactive for ionotropic AMPA receptors as well as metabotropic mGluR6 receptors (83-85). In figure 11 (right panel) immunoreactivity for GluR2/3, an ionotropic AMPA subunit, appears at an invaginating, ON-type ribbon contact in cat. Similarly in teleost retinas, ON-center bipolar cells are immunoreactive for ionotropic kainate receptors (86, 87). Particularly in mammals, no physiological role has been suggested for these conventional ionotropic receptors, usually associated with OFF bipolar cells, but also seen in ON-center bipolar cells. In giant danio Wong and Dowling find that bistratified cone bipolar cells mix ON-type and OFF-type glutamate receptor mechanisms, and utilize both transporter-like receptors and AMPA/kainate receptors in generating ON and OFF color responses respectively to different spectral stimuli (88).

Figure 11.Immunostaining for the ionotropic glutamate receptor GluR1 in bipolar cell dendrites contacting cone pedicles in cat retina. Red arrows point to flat contacts, the black arrow points to an invaginating contact, and the arrowheads point to synaptic ribbons in the cone pedicle. The illustration is from Qin and Pourcho, 1999 (261).

Figure 12. Immunostaining for ionotropic glutamate receptors in the dendritic tips of cat bipolar cells. GluR6/7 subunits are found in kainate receptors. GluR2/3 subunits are found in AMPA receptors. The red arrow (left, GluR6/7) points to a immuno-stained flat contact. The red arrow (right, GluR2/3) points to an immuno-stained invaginating contact. Letter labels are invaginating bipolar (ib), horizontal cell lateral element (h), and rod (r). The illustration is from Vardi et al., 1998 (83).

Ionotropic glutamate responses of OFF bipolar cells

Like ON bipolar cells, OFF bipolar cells express more than one type of glutamate receptor, though all are ionotropic. There are three principal types of ionotropic glutamate receptors (AMPA, kainate, and NMDA) as originally defined by agonist selectivity. Though immunocytochemical studies (84, 89, 90) and in situ hybridization (91) have identified specific NMDA receptor subunits in the outer retina, OFF bipolar cells have never been observed to utilize NMDA receptors in the generation of light responses. OFF bipolar cells selectively express either AMPA or kainate receptors (92, 93). These receptors resensitize at different rates after exposure to glutamate (Fig. 13), and as a result, emphasize different temporal characteristics of the light signal. Kainate-type glutamate receptors transfer the sustained characteristics of the visual stimulus. AMPA receptors are more selective for the transient components of the signal (92). In ground squirrel retina bipolar cells are selective for one or the other (93). The situation is interesting in so far as neurons using kainate receptors exclusively are rare in the central nervous system. Nonetheless, AMPA and kainate receptors on retinal bipolar cells are pharmacologically well-behaved. Bipolar-cell AMPA-type responses can be selectively suppressed by the lipophilic AMPA receptor antagonist GYKI 52466 (94). Conversely, bipolar-cell kainate-type responses are blocked by the desensitizing kainate receptor agonist SYM 2081 (95).

Figure 13. Different OFF bipolar cells re-sensitize at different rates after glutamate treatment. In whole cell patch recordings from ground squirrel retina, bipolar cells b3 and b2 are desensitized by an initial glutamate pulse (0). The time course of recovery is measured by responses to a second pulse after different delays. Type b3 (Fig. 16) bipolar cells utilize kainate-type glutamate receptors and require several seconds for complete recovery. Type b2 bipolar cells (Fig. 16) utilize AMPA-type glutamate receptors and recover 100 times faster. The illustration is from DeVries, 2000 (92, 93).

While all retinas contain ON and OFF bipolar cell pathways, it is easy to imagine that among these pathways natural selection might cause a divergence in the expression of dendritic glutamate receptor types depending on the visual requirements of the species. In agreement with this hypothesis, species-specific differences between ON and OFF bipolar cell dendritic glutamate responses have been found. For example, ionotropic glutamate channels with transporter-like pharmacology occur exclusively in ON type bipolar cells in fish retinas. Conversely in salamander, OFF bipolar cells utilize only AMPA receptors (96). This may also be the case in zebrafish retina where dissociated cells fail to respond to the kainate agonist SYM 2081 (86) and electroretinographic OFF responses (d-waves) are blocked by the AMPA antagonist GYKI 52466 (97). One might expect also that even within the broad classes of AMPA and kainate receptors, subforms may have evolved to fit particular visual niches. In salamander retina indeed, there are separate classes of AMPA receptors postsynaptic to rods and to cones (96, 98).

3 Bipolar-cell axons: ON and OFF lamination in the inner plexiform layer

In work performed at the National Institutes of Health in the mid 1970s (99, 100), it was noted that the ON or OFF property of cat retinal ganglion cells was related to the level of stratification of dendrites within the retinal inner plexiform layer. This led to a general scheme for ON and OFF layering illustrated in figure 14. The dendrites of OFF-center ganglion cells always arborize distal to the dendrites of ON-center ganglion cells. The zone of OFF-center dendritic arborization is called sublaminaa, while the zone of ON-center dendritic arborization is called sublaminab (Fig. 14). Within each sublamina ganglion cells make selective contacts with ON- or OFF-type bipolar cells. The pattern of ON and OFF layering of bipolar cell synaptic terminals and ganglion cell dendrites has proved to be a consistent pattern among all vertebrate retinas examined (101, 102). ON and OFF layering is particularly pronounced in retinas where ganglion cell types are predominantly monostratified. However, in more anatomically complex retinas, (i.e., turtle) with multistratified and/or diffusely stratified ganglion cell types, the ON vs. OFF layering pattern applies to monostratified cells only. The physiology of cells with processes ramifying throughout the IPL is more difficult to predict based on morphology alone (103).

Figure 14. Layering of ON and OFF bipolar cell axons in the cat inner plexiform layer (IPL). OFF ganglion cell (GC and GC) dendrites and OFF cone bipolar cell axons (OFF cb) co-stratify in sublamina a of the IPL. ON bipolar axons (ON cb) and ON ganglion cell dendrites co-stratify in sublamina b of the IPL. These are the parallel ON and OFF cone pathways that originate with bipolar-cell dendritic contacts with cones. The illustration is modified from Nelson et al, 1978 (100).

Stratification of cone bipolar cell axon terminals

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Bateman, I.J. and Munro, A. An Experiment on Risky Choice Amongst Households, The Economic Journal, 115:502, pp 176-189 (2005)

Baumann, A.C., Osman, M., Burton, M.P. and Lumley, S. Understanding Western Australian Consumers' Voews: Acceptance of Food Produced Using Gene Technology, Environmental Science and Pollution Research, 12:1, p 56 (2005)

Brouwer, R. and Bateman, I.J. Temporal stability and transferability of models of willingness to pay for flood control and wetland conservation, Water Resources Research, 41: pp 1-6 (2005)

Brouwer, R. and Bateman, I.J. Benefits transfer of willingness to pay estimates and functions for health-risk reductions: a cross-country study, Journal of Health Economics, 24:3, pp 591-611 (2005)

Brown, B., Weersink, A. and de Loe, R.C. Measuring Financial Capacity and the Effects of Regulatory Changes on Small Water Systems in Nova Scotia, Canadian Water Resources Journal, 30:3, pp 197-210 (2005)

Burton, M.P. and Bencini, R. Consumer Acceptance of New Sheep Milk Cheeses, Australasian Agribusiness Review, 13: (2005)

Chambers, R.G. and Quiggin, J. Incentives and Standards in Agency Contracts, Journal of Public Economic Theory, 7:2, pp 201-228 (2005)

Chambers, R.G. and Quiggin, J. Output Price Subsidies in a Stochastic World, American Journal of Agricultural Economics, 87:2, pp 501-508 (2005)

Chambers, R.G. and Melkonyan, T.A. Eliciting the core of a supermodular capacity, Economic Theory, 26:1, pp 203-209 (2005)

Chambers, R.G. and Quiggin, J. Linear-risk-tolerant, invariant risk preferences, Economics Letters, 86:3, pp 303-309 (2005)

Doole, G.J. Optimal management of the New Zealand longfin eel (Anguilla dieffenbachii), Australian Journal of Agricultural and Resource Economics, 49:4, pp 395-411 (2005)

Flugge, F.A. and Schilizzi, S.G.M. Greenhouse gas abatement policies and the value of carbon sinks: Do grazing and cropping systems have different destinies?, Ecological Economics, 55:4, pp 584-598 (2005)

Fraser, I. and Fraser, R. Targeting Monitoring Resources to Enhance the Effectiveness of the CAP, EuroChoices, 4:3, pp 22-27 (2005)

Georgiou, S. and Bateman, I.J. Revision of the EU Bathing Water Directive: economic costs and benefits, Marine Pollution Bulletin, 50:4, pp 430-438 (2005)

Gilmour, J.K., Letcher, R.A. and Jakeman, A.J. Analysis of an integrated model for assessing land and water policy options, Mathematics and Computers in Simulation, 69:1-2, pp 57-77 (2005)

Hart, R. and Latacz-Lohmann, U. Combating moral hazard in agri-environmental schemes: a multiple-agent approach, European Review of Agricultural Economics, 32:1, pp 75-91 (2005)

Henderson, B. and Kingwell, R.S. Rainfall and Farm Efficiency Measurement for Broadacre Agriculture in South-Western Australia, Australasian Agribusiness Reivew, 13: (2005)

John, M.B., Pannell, D.J. and Kingwell, R.S. Climate change and the economics of farm management in the face of land degradation: Dryland salinity in Western Australia, Canadian Journal of Agricultural Economics, 53:4, pp 443-459 (2005)

Kingwell, R.S. and Pannell, D.J. Economic trends and drivers affecting the grainbelt of Western Australia to 2030, Australian Journal of Agricultural Research, 56:6, pp 553-561 (2005)

Kingwell, R.S. Institutional Change and Plant Variety Provision in Australia, Australasian Agribusiness Reivew, 13: (2005)

Kingwell, R.S. Future Broadacre Farming Systems - a personal view, Connections, 1:Autumn 2005 (2005)

Lefroy, E.C., Flugge, F.A., Avery, A. and Hume, I. Potential of current perennial plant-based farming systems to deliver salinity management outcomes and improve prospects for native biodiversity: a review, Australian Journal of Experimental Agriculture, 45:11, pp 1357-1367 (2005)

Llewellyn, R.S., Pannell, D.J., Lindner, R.K. and Powles, S.B. Targeting key perceptions when planning and evaluating extension, Australian Journal of Experimental Agriculture, 45:12, pp 1627-1633 (2005)

Lobb, A.E. and Fraser, R.W. Implications of Recent Australian Wheat Industry Developments for Domestic and Overseas Prices, Journal of International Agricultural Trade and Development, 1:2, pp 93-108 (2005)

Merritt, W.S., Croke, B.F.W. and Jakeman, A.J. Sensitivty testing of a model for exploring water resources utilisation and management options, Environmental Modlling & Software, 20:8, pp 1013-1030 (2005)

Monjardino, M., Pannell, D.J. and Powles, S.B. The economic value of glyphosate-resistant canola in the management of two widespread crop weeds in a Western Australian farming system, Agricultural Systems, 84:3, pp 297-315 (2005)

Pannell, D.J. Farm, food and resource issues: politics and dryland salinity, Australian Journal of Experimental Agriculture, 45:11, pp 1471-1480 (2005)

Pannell, D.J. Voluntary versus Regulatory Approaches to Protecting the Environment in Rural Areas, Farm Policy Journal, 2:3, pp 1-9 (2005)

Pepper, C., Mccann, L.M.J. and Burton, M.P. Valuation study of urban busland at Hartfield Park, Forrestfield, Western Australia, Ecological Management & Restoration, 6:3, pp 190-196 (2005)

Potter, N.J., Zhang, L., Milly, P.C.D., McMahon, T.A. and Jakeman, A.J. Effects of rainfall seasonality and soil moisture capacity on mean annual water balance for Australian catchments, Water Resources Research, 41:6, pp 1-11 (2005)

Ridley, A. and Pannell, D.J. An Investment Framework for Managing Dryland Salinity in Australia, Farm Policy Journal, 2:4, pp 39-49 (2005)

Ridley, A.M. and Pannell, D.J. The role of plants and plant-based research and development in managing dryland salinity in Australia, Australian Journal of Experimental Agriculture, 45:11, pp 1341-1355 (2005)

Rigby, D. and Burton, M.P. Preference heterogeneity and GM food in the UK, European Review of Agricultural Economics, 32:2, pp 269-288 (2005)

Sadoddin, A., Letcher, R.A., Jakeman, A.J. and Newham, L.T.H. A Bayesian decision network approach for assessing the ecological impacts of salinity management, Mathematics and Computers in Simulation, 69:1-2, pp 162-176 (2005)

Sudmeyer, R. and Flugge, F.A. The economics of managing tree-crop competition in windbreak and alley systems, Australian Journal of Experimental Agriculture, 45:11, pp 1403-1411 (2005)

Ticehurst, J.L., Croke, B.F.W. and Jakeman, A.J. Model design for the hydrology of tree belt plantations on hillslopes, Mathematics and Computers in Simulation, 69:1-2, pp 188-212 (2005)

Weersink, A. and Wossink, A. Lessons from agri-environmental policies in other countries for dealing with salinity in Australia, Crop Protection, 45:11, pp 1481-1493 (2005)

Weersink, A., Llewellyn, R.S. and Pannell, D.J. Economics of pre-emptive management to avoid weed resistance to glyphosate in Australia, Crop Protection, 24:7, pp 601-693 (2005)

Weersink, A., Pannell, D.J., Fulton, M. and Meyer-Aurich, A. Agriculture's Likely Role in Meeting Canada's Kyoto Commitments, Canadian Journal of Agricultural Economics, 53:4, pp 425-441 (2005)

White, B. An Economic Analysis of Ecological Monitoring, Ecological Economics, 189:3-4, pp 241-250 (2005)

White, B. and Dawson, P.J. Measuring Price Risk on UK Arable Farms, Journal of Agricultural Economics, 56:2, pp 239-252 (2005)

Drewry, J.J., Newham, L.T.H., Greene, R.S.B., Jakeman, A.J. and Croke, B.F.W. An Approach to Assess and Manage Nutrient Loads in Two Coastal Catchments of the Eurobodalla Region, NSW, Australia, MODSIM05, Melbourne, Modelling and Simulation Society of Australia and New Zealand, 1: pp 2658-2664 (2005)

Hailu, A. and Schilizzi, S.G.M. Learning in a "Basket of Crabs": An Agent-Based Computational Model of Repeated Conservation Auctions, Nonlinear Dynamics and Heterogeneous Interacting Agents, Germany, Springer-Verlag, 8th: pp 27-39 (2005)

Ticehurst, J.L., Rissik, D., Letcher, R.A., Newham, L.H.T. and Jakeman, A.J. Development of Decision Support Tools to Assess the Sustainability of Coastal Lakes, MODSIM05, Melbourne, Modelling and Simulation Society of Australia and New Zealand, 1: pp 2414-2420 (2005)

Lindner, R.K. Impacts of Mud Crab Hatchery Technology in Vietnam, :1, pp 1-68, Canberra (2005)

Raitzer, D.A. and Lindner, R.K. Review of the Returns to ACIAR's Bilateral R&D Investments, 1:35, pp 1-64, Canberra (2005)

Catts, O. and Zurr, I. The Art of the Semi Living, Art et Biotechnologies, ed Poissant, L. and Daubner, E., Quebec, Presses de lniversite du Quebec, pp 99 - 115 (2005)

Chisholm, J.S., Burbank, V.K., Coall, D.A. and Gemmiti, F. Early Stress: Perspectives from Developmental Evolutionary Ecology, Origins of the Social Mind, ed Ellis, B.J., Bjorklund, D.F., New York, The Guilford Press, pp 1-525 (2005)

Lynch, G.S., Shavlakadze, T. and Grounds, M.D. Strategies to reduce age-related skeletal muscle wasting, Ageing Interventions and Therapies, ed Rattan, S.I.S., Singapore, World Scientific, pp 63-84 (2005)

Wessen, K. Simulating Human Origins and Evolution, UK, Cambridge University Press (2005)

Arfuso, F., McGeachie, J.K. and Meyer, G.T. A quantitative study of blood capillary formation (angiogenesis) concomitant with parenchymal tissue differentiation, Endothelium, 12: pp 171-177 (2005)

Bates, K.A., Harvey, A.R., Carruthers, M. and Martins, R.N. Androgens, andropause and neurodegeneration: exploring the link between steroidogenesis, androgens and Alzheimer's disease, Cellular and Molecular Life Sciences, 62: pp 281-292 (2005)

Camelo, S., Kezic, J. and McMenamin, P.G. Anterior chamber associated immune deviation: a review of the anatomical evidence for the afferent arm of this unusual experimental model of ocular immune responses, Clinical and Experimental Ophthalmology, 33: pp 426-432 (2005)

Charles, A.K., Hisheh, S., Liu, D., Rao, R.M., Waddell, B.J., Dickinson, J.E., Rao, A.J. and Dharmarajan, A.M. The expression of apoptosis related genes in the first trimester human placenta using a short term in vitro model, Apoptosis, 10:1, pp 135-140 (2005)

Chen, X., Milne, N. and O'Higgins, P. Morphological variation of the thoracolumbar vertebrae in Macropodidae and its functional relevance, Journal of Morphology, 266: pp 167-181 (2005)

Chinnery, H., Kezic, J., Yeung, S. and McMenamin, P.G. The cause of a band-like opacity in the corneas of abattoir acquired pig eyes, Clinical and Experimental Ophthalmology, 33: pp 665-674 (2005)

Chisholm, J.S., Quinlivan, J.A., Petersen, R.W. and Coall, D. Early stress predicts age at Menarche and first birth, adult attachment and expected lifespan, Human Nature, 16:3, pp 233-265 (2005)

Dixon, K.J., Hilber, W., Speare, S., Willson, M.L., Bower, A.J. and Sherrard, R.M. Post-lesion transcommissural olivocerebellar reinnervation improves motor function following unilateral pedunculotomy in the neonatal rat, Experimental Neurology, 196: pp 254-265 (2005)

Eastwood, P.R., Platt, P.R., Shepherd, K., Maddison, K. and Hillman, D.R. Collapsibility of the upper airway at different concentrations of propofol anesthesia, Anesthesiology, 103:3, pp 470-477 (2005)

Eppler, E., Walch, M., Latinovic-Golic, S., Dumrese, C., Filgueira, L. and Groscurth, P. Human dendritic cells process and present Listeria antigens for in vitro priming of autologous CD4+ T lymphocytes, Histochemistry and Cell Biology, 123: pp 169-178 (2005)

Fournier, B., Lohof, A.M., Bower, A.J., Mariani, J. and Sherrard, R.M. Developmental modifications of olivocerebellar topography: the granuloprival cerebellum reveals multiple routes from the inferior olive, The Journal of Comparative Neurology, 490: pp 85-97 (2005)

Fox, S.A., Kusmiaty, D., Loh, S., Dharmarajan, A.M. and Garlepp, M.J. Cisplatin and TNF-a downregulate transcription of Bcl-xL in murine malignant mesothelioma cells, Biochemical and Biophysical Research Communications, 337: pp 983-991 (2005)

Franklin, D., Freedman, L. and Milne, N. Three-dimensional technology for linear morphological studies: a re-examination of cranial variation in four southern African indigenous populations, Homo-Journal of Comparative Human Biology, 56: pp 17-34 (2005)

Franklin, D., Freedman, L. and Milne, N. Sexual dimorphism and discriminant function sexing in indigenous South African crania, Homo - Journal of Comparative Human Biology, 55: pp 213-228 (2005)

Gaudieri, S., De Santis, D., McKinnon, E., Moore, C., Nolan, D., Witt, C.S., Mallal, S.A. and Christiansen, F.T. Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression, Genes and Immunity, 1: (2005)

Gaudieri, S., Nolan, D., McKinnon, E., Witt, C.S., Mallal, S. and Christiansen, F.T. Associations between KIR epitope combinations expressed by HLA-B/-C haplotypes found in an HIV-1 infected study population may influence NK mediated immune responses, Molecular Immunology, 42: pp 557-560 (2005)

Grounds, M. The Wonder of Stem Cells and their Clinical Applications, Australian Biochemist, 36:1, p 3 (2005)

Grounds, M.D., Davies, M., Torrisi, J., Shavlakadze, T., White, J. and Hodgetts, S. Silencing TNF alpha activity by using Remicade or Enbrel blocks inflammation in whole muscle grafts: an in vivo bioassay to assess the efficacy of anti-cytokine drugs in mice, Cell and Tissue Research, 320: pp 509-515 (2005)

Grounds, M.D., Sorokin, L. and White, J. Strength at the extracellular matrix-muscle interface, Scandinavian Journal of Medicine & Science in Sports, 15: pp 381-391 (2005)

Grove, J.R., Wilkinson, A., Dawson, B.T., Eastwood, P.R. and Heard, N.P. Effects of exercise on subjective aspects of sleep during tobacco withdrawal, Australian Psychologist, 41:8, pp 1-8 (2005)

Harriso, G.A., Schmitt, L.H. and Harrison, C.B.G. Reflections on Aboriginal Health, Society, Biology & Human Affairs, 70:2, pp 53-55 (2005)

Hayes, S., Taylor, R. and Paterson, A. Forensic Facial Approximation: An Overview of Current Methods Used at the Victorian Institute of Forensic Medicine/Victoria Police Criminal Identification Squad, The Journal of Forensic Odonto-Stomatology, 23:2, pp 45-50 (2005)

Haynes, M.J., Cala, L.A., Melsom, A., Mastaglia, F.L., Milne, N. and McGeachie, J.K. Posterior ponticles and rotational stenosis of vertebral arteries. A pilot study using doppler ultrasound velocimetry and magnetic resonance angiography, Journal of Manipulative and Physiological Therapeutics, 28:5, pp 323-329 (2005)

Hill, K. and Eastwood, P.R. Respiratory muscle training: the con argument, Chronic Respiratory Disease, 2: pp 223-224 (2005)

Hu, Y., Leaver, S.G., Plant, G.W., Hendriks, W.T.J., Niclou, S.P., Verhaagen, J., Harvey, A.R. and Cui, Q. Lentiviral-mediated transfer of CNTF to Schwann cells within reconstructed peripheral nerve grafts enhances adult retinal ganglion cell survival and axonal regeneration, Molecular Therapy, 11:6, pp 906-915 (2005)

Kam, D.W.R., Charles, A.K. and Dharmarajan, A.D. Caspase-14 expression in the human placenta, Reproductive BioMedicine Online, 11:2, pp 236-243 (2005)

Kidd, R. and Oxnard, C. Little foot and big thoughts - a re-evaluation of the Stw573 foot from Sterkfontein, South Africa, Homo-Journal of Comparative Human Biology, 55: pp 189-212 (2005)

Kovar, J., Willett, K.E., Hislop, A. and Sly, P.D. Impact of postnatal glucocorticoids on early lung development, Journal of Applied Physiology, 98: pp 881 - 88 (2005)

Laird, R., Dawkins, R.L. and Gaudieri, S. Use of the genomic matching technique to complement multiplex STR profiling reduces DNA profiling costs in high volume crimes and intelligence led screens, Forensic Science International, 151: pp 249-257 (2005)

Lareu, R.R., Lacher, M.D., Friis, R.R. and Dharmarajan, A.M. Cloning and characterization of a novel zinc finger protein (rZFP96) in the rat corpus luteum, Biochimica et Biophysica Acta, 1732: pp 69-75 (2005)

Lee-Pullen, T. and Grounds, M. The reality of skeletal muscle stem cells, Australian Biochemist, 36:1, pp 4-6 (2005)

Lee-Pullen, T.F. and Grounds, M.D. Muscle-Derived Stem Cells: Implications for Effective Myoblast Transfer Therapy, IUBMB Life, 57:11, pp 731-736 (2005)

Lohof, A.M., Mariani, J. and Sherrard, R.M. Afferent-target interactions during olivocerebellar development: transcommissural reinnervation indicates interdependence of Purkinje cell maturation and climbing fibre synapse elimination, European Journal of Neuroscience, 22: pp 2681-2688 (2005)

Lucas, A.D., Gaudieri, S., Rauch, A., Nolan, D. and Mallal, S.A. Cellular Tropism of HIV-1 Mediated and Constrained by Coreceptor Dependencies, The Journal of Viral Entry, 1:1, pp 17-27 (2005)

Maddison, K.J., Shepherd, K.L., Hillman, D.R. and Eastwood, P.R. Function of the lower isophageal sphincter during and after high-intensity exercise, Medicine & Science in Sports & Exercise, 37:10, pp 1728-1733 (2005)

McMenamin, P.G. A simple interactive teaching aid for medical undergraduates studying the brachial plexus, Medical Teacher, 27:2, pp 169-171 (2005)

Meagher, J., Zellweger, R. and Filgueira, L. Functional dissociation of the basolateral transcytotic compartment from the apical phago-lysosomal compartment in human osteoclasts, Journal of Histochemistry & Cytochemistry, 53:5, pp 665-570 (2005)

Merino, M.L., Milne, N. and Vizcaino, S.F. A cranial morphometric study of deer (Mammalia, Cervidae) from Argentina using three-dimensional landmarks., Acta Theriologica, 50:1, pp 91-108 (2005)

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