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. Something must have happened to the responses in between photoreceptors and ganglion cells. 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 function.
Werblin and Dowling (1969) posited that retinal bipolar cells lacked impulse activity, and that they processed visual signals through integration of synaptic and voltage-gated currents alone. They also proposed that retinal bipolar cells come in two fundamental varieties: ON-center and OFF-center as illustrated in Fig. 1. Both types display a surround region in their receptive field that is of opposite polarity to the center, similar to the classic, antagonistic center-surround organization earlier described for ganglion cell receptive fields (Kuffler, 1953) (see chapter on ganglion cell physiology). ON-center bipolar cells are depolarized by small spot stimuli positioned in the receptive field center. OFF-center types 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 (Werblin and Dowling, 1969). ON-OFF responses first occur among amacrine cells, neurons postsynaptic to bipolar cells.
Anatomical investigations of bipolar cells reveal a variety (4-13 depending on species) of different morphological types (Kolb et al., 1981; Euler et al., 1996; Connaughton and Nelson, 2000; Wu et al., 2000), significantly more than merely the two ON or OFF types that early physiology implied (Fig. 2). Nonetheless all of these morphological varieties are either ON- or OFF-types. Their diversity results from other factors, such as differing connectivity with photoreceptors and differing postsynaptic targets. Some bipolar cells are postsynaptic to only rods, others 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 not selective (Scholes, 1975; Ishida et al, 1980; Mariani, 1984). Different bipolar types express different glutamate receptors at subsynaptic sites. Bipolar cell terminals are either mono- or multistratified, depending on the location of synaptic boutons in the inner plexiform layer (see below). Differing terminal position and morphology within the inner plexiform layer (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’ 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.
Fig. 2. Bipolar cell types in human retina
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 (Ayoub and Copenhagen, 1991); yet bipolar cells react to this stimulus with two different responses, ON-center (glutamate hyperpolarization) and OFF-center (glutamate depolarization), each associated with different post-synaptic conductance mechanisms. These different, glutamate-gated, bipolar-cell responses are associated with expression of either ionotropic (iGluR) or metabotropic (mGluR) glutamate receptor types on bipolar cell dendrites.
ON bipolar cells
The conductance of ON bipolar cells increases in the light, whereas OFF bipolar cell conductance decreases (Nelson, 1973; Toyoda, 1973). The conductance decrease of OFF bipolar cells is easily explained as a loss of excitation by glutamate, as light inhibits glutamate release from photoreceptors (Dacheux and Miller, 1976). The positive reversal potential of the ON bipolar cell light response, coupled with a conductance increase (Nelson, 1973; Lasansky, 1992), implies that glutamate blocks a cation-permeable channel. This was the first evidence of what we now understand as metabotropic glutamate receptors. These receptors do not form ion channels themselves, but act as isolated antennae on the cell surface sensing glutamate and activating intracellular pathways and mechanisms that can indirectly affect membrane potential. Metabotropic receptors have been identified on the axon terminals of both photoreceptors (Hirasawa et al., 2002) and bipolar cells (Awatramani and Slaughter, 2001) where they serve as autoreceptors regulating neurotransmitter release. However, the expression of one specific mGluR on 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.
Slaughter and Miller (1981) 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) selectively blocks the light responses of ON bipolar cells. In ON bipolar cells, APB acts as a substitute for photoreceptor-released glutamate (Fig. 3). Thus, ON bipolar cells utilize a metabotropic pathway to sense light-induced variations in photoreceptor glutamate. The metabotropic receptor has been identified as mGluR6 (Nakajima et al., 1993; Nomura et al., 1994). Transgenic knockout mice lacking the mGluR6 gene lack the electroretinographic b-wave (see Fig. 4, and later section), a component associated with ON bipolar activity (Masu et al., 1995).
Followup immunocytochemical localization shows staining for this receptor in the invaginating dendritic tips of monkey bipolar cells (Fig. 5). Invaginating bipolar cells are thought to be ON types in primate retina. In addition to mGluR6, the G-protein Go is cytoplasmically localized in the dendritic tips of ON bipolar cells as shown in figure 6 from Vardi and co-workers work (1993). Removal of the alpha subunit (Gao) by knockout results in b-wave loss (Dhingra et al., 2000), similar to the mGluR6 knockout. This suggests that Go is directly involved in the intracellular pathway following mGluR6 activation.
This at first suggested that the closure of ion channels following glutamate binding onto mGluR6, activated Go, and consequently phosphodiesterase, resulting in the increased hydrolysis of cGMP (Nawy and Jahr, 1990). However, the exact cascade by which this happens is now less clear, as blocking phosphodiesterase (PDE) activity, or adding non-hydrolyzable cGMP analogs, does not inhibit the glutamate responses generated through APB-receptors (Nawy, 1999). Thus, removal of cGMP appears not to be required for channel closure (Nawy, 1999). Calcium ions are a further modulator of the ON bipolar ion channel. Calcium ions, entering through the ion channel closed by glutamate (Yamashita and Wassle, 1991; Nawy, 2000) affect channel function, either by directly down regulating the channel (Thoreson and Miller, 1993; Nawy, 2000) or by activating calcium-dependent enzymes, such as CaMKII (Walters et al., 1998; Shiells and Falk, 2000), which modulate ion channel conductance.
Metabotropic receptors for ON-center bipolar cells have sustained and transient subtypes (Awatramani and Slaughter, 2000). 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 (Enroth-Cugell and Robson, 1966), may have their origin, at least in part, in the type of glutamate receptor expressed on bipolar cells which innervate them (Demb et al., 2001).
Ionotropic glutamate receptors contribute to the light responses of some ON-center bipolar cells. When photoreceptor glutamate binds to these receptors, a Cl- conductance is activated, hyperpolarizing the cells in the dark (Fig. 7). Release from this inhibition occurs in the light, with the decrease in glutamate released from photoreceptors, allowing the bipolar cells to depolarize (Fig. 7). The receptor is related to glutamate transporters, and requires [Na+]o. Thus far this mechanism has been found only in teleost bipolar cells (Grant and Dowling, 1995; Grant and Dowling, 1996; Connaughton and Nelson, 2000), though it is reported in both turtle and salamander photoreceptors (Tachibana and Kaneko, 1988a; Picaud et al., 1995; Grant and Werblin, 1996) and is also present in mammalian central nervous system (Otis and Jahr, 1998). Some teleost bipolar cells contain both the APB and the ionotropic (transporter-like) receptors on their dendrites, while other ON-cells express either the metabotropic or the ionotropic receptor separately (Grant and Dowling, 1996; Connaughton and Nelson, 2000). The ionotropic mechanism is used for sustained transmission between cones and bipolar cells (Saito et al., 1981), and is likely to be a fast mechanism as compared to the metabotropic pathway, which is often relatively slow (Nelson, 1973).
ON-center bipolar cells of mammals are immunoreactive for ionotropic AMPA receptors as well as metabotropic mGluR6 receptors (Vardi et al, 1998, see Fig. 9, GluR2/3). Similarly in teleost retinas, ON-center bipolar cells are immunoreactive for ionotropic kainate receptors (Peng et al, 1995; Nelson et al, 2000). No physiological role has been suggested for these conventional ionotropic receptors seen in ON-center bipolar cells.
OFF bipolar cells
Like ON bipolar cells, OFF bipolar cells express more than one type of glutamate receptor, though all are ionotropic. Flat contacts are characteristic of OFF bipolar cells. AMPA receptor subunits are seen in flat contacts (GluR1, Fig. 8), as are kainate receptor subunits (GluR6/7, Fig. 9). There are three principal types of ionotropic glutamate receptors (AMPA, kainate, and NMDA) as defined by agonist selectivity. Though immunocytochemical studies (Hughes, 1997; Wenzel et al., 1997; Pourcho et al., 2001) and in situ hybridization (Hartveit et al., 1994) 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 may selectively utilize either AMPA or kainate receptors in the generation of light responses (DeVries and Schwartz, 1999; DeVries, 2000). These receptors resensitize at different rates after exposure to glutamate (Fig. 10), 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 (DeVries, 2000). The situation is interesting in so far as neurons using kainate receptors exclusively are rare in the central nervous system. AMPA and kainate receptors on retinal bipolar cells are pharmacologically well behaved. Bipolar-cells with AMPA-type responses are suppressed by the selective lipophilic AMPA receptor antagonist GYKI 52466 (Paternain et al., 1995). Conversely, bipolar cells with kainate-type responses are blocked by the selective desensitizing kainate receptor agonist SYM 2081 (Jones et al., 1997).
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 (Maple et al., 1999). This may also be the case in zebrafish retina where dissociated cells fail to respond to the kainate agonist SYM 2081 (Nelson et al., 2001) and electroretinographic OFF responses (d-waves) are blocked by the AMPA antagonist GYKI 52466 (Wesolowska et al., 2002). 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 (Kim and Miller, 1993; Maple et al., 1999). Thus a 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.
3. ON and OFF stratification in the inner plexiform layer.
In work performed at the National Institutes of Health in the mid 1970s (Famiglietti and Kolb, 1976; Nelson et al., 1978), 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 (IPL). This led to the general scheme for ON and OFF layering illustrated in figure 11. 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 sublamina a, while the zone of ON-center dendritic arborization is called sublamina b(Fig. 11). 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 finding among all vertebrate retinas examined (Bloomfield and Miller, 1986; Amthor et al., 1989). 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 (Ammermuller and Kolb, 1995).
Stratification of cone bipolar cell axon terminals
The axon terminals of ON and OFF bipolar cells ramify in distinct IPL layers, where they are presynaptic to ON- and OFF-type ganglion cells, respectively. The axon terminal arborizations of OFF-type cone-contacting bipolar cells lie in sublamina a, where they synapse with the dendrites of OFF-type ganglion cells, while the axon terminal arborizations of ON-type cone contacting bipolar cells lie in sublamina bwhere they contact the dendrites of ON-center ganglion cells. Synapses between OFF-type bipolar terminals and ganglion cell dendrites in sublamina a, and ON-type cells in sublamina b, have been observed electron-microscopically (Kolb, 1979; Nelson and Kolb, 1983; McGuire et al., 1984; Cohen and Sterling, 1991; Kolb and Dekorver, 1991; Kolb and Nelson, 1993). Synapses between pairs of bipolar and ganglion cells with mismatched response polarity are never observed, even where processes come in close proximity (Kolb, 1979).
In salamander retina, Awatramani and Slaughter (Awatramani and Slaughter, 2000) have proposed a further refinement of the bipolar cell stratification scheme: cells with a glutamate receptor physiology emphasizing transients in the visual pattern are layered more toward the center of the IPL, while those with receptor patterns emphasizing sustained contrast are layered more towards IPL inner and outer edges. Such a pattern would be appropriate to the layering of the sustained X and transient Y type ganglion cells of the cat retina, as well as P and M cells of the primate retina. Wu et al (Wu et al., 2000) find a similar pattern in salamander, but attribute it to an elaboration of other circuitry elements, as bipolar cells with arbors in the mid-IPL tend to be cone dominated, emphasizing speed and transient response, whereas bipolar cells with axon terminals stratified at the inner and outer edges of the IPL process rod signals, which are relatively more lethargic (Wu et al., 2000).
Relatively exhaustive correlations of ON or OFF bipolar cell physiology with axonal stratification patterns are now available for several species. These involve measurements of light responses or, as a surrogate for light responses, dendritic glutamate responses, coupled with observations of axonal morphology through microelectrode staining. In rat retina, bipolar cell axon terminal arborization appears to obey perfectly the rule of ON and OFF layering (Euler et al., 1996).
In figure 12, rat bipolar cells are organized according to the IPL layer in which terminals arborize. The axons of cone bipolar cells 1-5 branch in the outer half of rat IPL. These cells responded with inward currents when stimulated with kainate. This is the response, and morphology, appropriate to OFF bipolar cells. Of a combined 15 recordings from types 1-5, only one cell responded to APB (DL AP-4), a glutamate agonist selective for ON center bipolar cells. Four cone bipolar cell types with axons branching in the inner half of rat IPL were identified (types 6-9, Fig. 12). In net 12 of 14 of cells of these types responded with outward currents to APB, whereas only one responded to kainate (Euler et al., 1996). This is a better than 90% compliance with the ON and OFF stratification rule for cone bipolar cell axon terminals in rat retina, and suggests that division between sublamina a (OFF layer) and sublamina b (ON layer) is about in the middle of the rat IPL (Fig. 12). A more limited set of recordings in cat and monkey retinas suggest also that there may be good adherence to ON and OFF stratification of bipolar terminals (Nelson and Kolb, 1983; Dacey and Lee, 1994). The salamander retina also appears to be in excellent compliance (Wu et al., 2000), as does carp (Famiglietti et al., 1977; Saito et al., 1985). However the relative thickness of sublaminas a and bvaries somewhat from species to species.
Bisublaminar orderliness breaks down to some extent in species where multistratified bipolar cell axons are common. While multistratified cells exist in monkeys and cats (Kolb et al., 1981; Mariani, 1983, see Fig. 2-GBB), these types are much more common in other vertebrates (birds, reptiles, and fishes) or cone dominated mammals such as squirrels. Multistratified types have been shown to be cone contacting bipolar cells (Scholes, 1975; Mariani, 1983) and so may be characteristic of cone-dominated species. If broad or multistratified bipolar terminals are restricted to either the ON or the OFF sublamina (i.e. all boutons within the same sublamina), the ON and OFF stratification rules apply. However, if the axonal stratification pattern crosses the ON-OFF boundary, the cells may be either ON-type or OFF-type (Ammermuller and Kolb, 1995; Connaughton and Nelson, 2000; Wu et al., 2000). In some cases such multistratified bipolar cells may even express both physiologies (Wu et al., 2000). Stratification patterns of bipolar axon terminals of the zebrafish retina represent this more general vertebrate pattern (Fig. 12). Bipolar cells with 1 or 2 terminal boutons restricted either to sublamina a or to sublamina b obey the ON and OFF stratification rule. OFF cells branching in sublamina a express AMPA/KA type receptors. ON cells branching in sublamina b express either or both of two inhibitory glutamate mechanisms, ionotropic (Iglu, transporter-like chloride current) or metabotropic (APB receptor). Multistratified bipolar cells with boutons in both sublaminas may be either ON or OFF types. Multistratified ON types use only Iglu, the transporter-like chloride current (Connaughton and Nelson, 2000).
Stratification of rod bipolar cell axon terminals
Rod bipolar cells represent a unique case. These cells are easily identified in mammals and fish (Cajal, 1972). Judged by the axonal stratification pattern and contacts with photoreceptors, there is only a single class of rod bipolar cell in mammals (Kolb, 1970; Cajal, 1972). The bulbous axon arborizes deep in the ON sublamina of the IPL, just adjacent to ganglion cells (Fig. 12, rb). The rod bipolar is an ON-type cell (Dacheux and Raviola, 1986) utilizing metabotropic APB-sensitive, glutamate receptors (Yamashita and Wässle, 1991; de la Villa et al., 1995). In fish, the comparable cell type is the Mb bipolar cell (Sherry and Yazulla, 1993). Rod bipolar cells are universally recognized by high immunoreactivity for protein kinase C (PKC) (Negishi et al., 1988; Greferath et al., 1990; Yamashita and Wässle, 1991; Kolb et al., 1993).
The rod bipolar cell does not contact ganglion cells directly in the mammalian retina. It is the AII amacrine cell (Kolb and Famiglietti, 1974; Nelson, 1982) that is the intermediary in transferring rod bipolar signals to ganglion cells. The AII cell achieves this through direct innervations of cone bipolar processes within the IPL, either by means of chemical synapses to OFF bipolar and ganglion cells (large arrow in sublamina a,Fig. 14) or by gap junctions between AII dendrites and ON cone bipolar axons (large arrow with red asterisk, Fig. 14). Cone bipolar cells also participate, even without amacrine intermediation, in transferring ON and OFF rod signals from distal to proximal retina. This occurs because of gap junctions between rods and cones, a pathway emphasized in higher mammals (Raviola and Gilula, 1973; Kolb, 1977; Nelson, 1977; Smith et al., 1986; Tsukamoto et al., 2001), or through direct dendritic contact of cone bipolar cells with rods (Lasansky, 1973; Jacobs et al., 1976; Stell, 1977; Ishida et al., 1980; Dacheux, 1982; Hack et al., 1999; Tsukamoto et al., 2001), a pathway particularly emphasized in non mammalian vertebrates.
4. Electrical properties, lateral inhibition, and synaptic release.
Voltage-gated currents
Retinal bipolar cells express a variety of voltage-gated currents. In general, these currents are carried by calcium (Ca2+) and/or potassium (K+) ions. Intracellular recordings show bipolar cells produce graded potentials in response to a light stimulus, but not action potentials (Werblin and Dowling, 1969). This finding is supported by several studies in which voltage-gated sodium currents were not identified in bipolar neurons (Lasater, 1988; Karschin and Wässle, 1990; Connaughton and Maguire, 1998). However, recent studies have reported voltage-gated sodium currents in some cone bipolar cells in rat (Pan and Hu, 2000) and goldfish (Zenisek et al., 2001). While not producing action potentials, these currents may serve to amplify synaptic events. They have not been seen in rod bipolar cells. However calcium-dependent action potentials have been identified in rod bipolar cells (Protti and Llano, 1998; Zenisek and Matthews, 1998). Thus, in some species, this subset of bipolar cells may utilize unorthodox action potentials.
All bipolar cells examined to date express inward Ca2+ currents in response to membrane depolarizations. The Ca2+ currents are either transient (T-type/low voltage activated) and/or sustained (L-type/high voltage activated). The expression of these different Ca2+ current types varies among vertebrate species. For example, in goldfish, L-type Ca2+ currents are present (Kaneko et al., 1991; Heidelberger and Matthews, 1992); whereas, mouse bipolar cells express only a transient T-type current (Kaneko et al., 1989; Kaneko et al., 1991). In salamander (Maguire et al., 1989) and zebrafish (Connaughton and Maguire, 1998), however, both T- and L-type Ca2+ channels are present, with the L-type localized to the axon terminal. Recordings of a zebrafish bipolar cell expressing both L-type and T-type Ca2+
currents appear in figure 15 (ICa).
A number of potassium (K+) currents have been identified in bipolar cells. Membrane depolarization typically elicits a combination of outward K+ currents. In goldfish (Kaneko and Tachibana, 1985) and tiger salamander retina (Lasansky, 1992), a slowly activating, delayed rectifying (IK) potassium current, modulated by dopamine (Fan and Yazulla, 2001), is present. In contrast, axolotl bipolar neurons (Tessier-Lavigne et al., 1988) express a rapidly activating, slowly inactivating IA current in response to depolarizing membrane potentials. Bipolar cells in fish, such as white bass and zebrafish, express one or the other of these two types of K+ currents, suggesting that these neurons can be differentiated into distinct populations based on the voltage-gated currents they express (Lasater, 1988; Connaughton and Maguire, 1998). Membrane depolarizations also elicit a calcium-dependent K+ current (IK(Ca)) that contributes to the overall outward current amplitude observed (Kaneko and Tachibana, 1985; Lasater, 1988; Connaughton and Maguire, 1998). Membrane hyperpolarizations elicit the slowly activating, inward rectifying (Ih) current (Kaneko and Tachibana, 1985; Lasater, 1988; Karschin and Wässle, 1990; Connaughton and Maguire, 1998). Examples of K+ currents evoked by membrane depolarization (IK, IA, IK(Ca)), or hyperpolarization (Isust, Ih) appear in figure 15. These were recorded in zebrafish retinal bipolar cells.
Inhibitory ligand-gated currents
As described above, light stimulation of the bipolar cell receptive field reveals characteristic center-surround antagonism, where the response of the center is of opposite polarity to the response of the surround. It is believed that the center component of the bipolar cell light response arises from direct glutamatergic inputs from photoreceptors, while the surround response is generated indirectly by horizontal-cell suppression of glutamate release from cones (Kamermans, 2001), and directly by inhibitory GABAergic and/or glycinergic inputs. These inputs generate signals of either hyperpolarizing or depolarizing polarity depending on the magnitude of the chloride (Cl-) gradient across the synaptic membranes (Vardi et al., 2000). Chloride-mediated ON and OFF responses to light have been observed in ON bipolars of tiger salamander (Lasansky, 1992). These components appear to originate with AMPA excitation of GABAergic and glycinergic inhibitory interneurons, rather than photoreceptors (Lasansky, 1992; Thoreson, 1993). Immunocytochemical studies show that bipolar-cell dendrites and terminals are surrounded by GABAergic processes. In the OPL, these processes belong to horizontal cells; whereas, in the IPL, GABAergic amacrine cell processes surround bipolar terminals as illustrated in the electron micrographs for both fish and cat (Figs. 16 and 17)(Marc et al., 1978; Marc and Liu, 2000; Freed et al., 1983; Pourcho and Goebel, 1983; Freed et al., 1987; Connaughton et al., 1999).
Physiological studies report bipolar cell processes are differentially sensitive to external GABA application (Fig. 18). GABA-evoked currents are typically greatest at the axon terminals (Tachibana and Kaneko, 1987; Tachibana and Kaneko, 1988b; Lukasiewicz et al., 1994), though smaller amplitude currents can be elicited from the soma and/or dendrites (Fig. 18). This suggests an inhibitory feedback circuit from neighboring amacrine cells (Tachibana and Kaneko, 1987; Tachibana and Kaneko, 1988b; Lukasiewicz et al., 1994; Lukasiewicz and Werblin, 1994) occurs through direct GABAergic input onto bipolar cell terminals. GABAergic inputs to bipolar dendrites may also occur indirectly, through a feedback synapse involving photoreceptors (Burkhardt, 1977; Kondo and Toyoda, 1983; Wu, 1986; Wu and Maple, 1998).
GABA application elicits a chloride (Cl-) current. Depending on the Cl- gradient either depolarization or hyperpolarization may result, though the most common result is hyperpolarization. GABA-elicited currents have both transient and sustained components. The transient response is mediated by GABAA receptors; while the sustained component results from the activation of GABAC receptors (Tachibana and Kaneko, 1987; Qian and Dowling, 1993; Feigenspan and Bormann, 1994; Qian and Dowling, 1995; Lukasiewicz and Wong, 1997; Lukasiewicz and Shields, 1998b; Lukasiewicz and Shields, 1998a; Vaquero and de la Villa, 1999; McGillem et al., 2000). The sustained components of GABAC responses last many minutes and the hyperpolarizing action is readily seen in voltage probe studies of dissociated bipolar cells (Nelson et al., 1999). The different time courses of GABAA and GABAC currents, and the different sensitivity to selective antagonists are illustrated for ferret bipolar cells in figure 19; the molecular properties of retinal GABA receptors are explained in another Webvision chapter (see chapter on GABAC receptors). GABAB receptors have been identified on the axon terminals of salamander and goldfish bipolar cells, where they reduce calcium influx (Maguire et al., 1989; Heidelberger and Matthews, 1991). Interestingly, though most bipolar cells appear to express both GABAA and GABAC receptors, it is the GABAC receptor that underlies 70-80% of GABA-elicited responses. Differential expression of GABAA and GABAC receptors would allow these cells to respond to a range of GABA concentrations and time courses within the synaptic cleft, as these different receptor types display collectively high sensitivity to long duration applications of low GABA doses (GABAC), and short duration applications of high GABA doses (GABAA) (Lukasiewicz and Wong, 1997; Lukasiewicz and Shields, 1998a).
GABA receptors affect the dynamics of retinal light responses (Freed, 1992; Frumkes and Nelson, 1995; Frumkes et al., 1995). GABAA antagonists cause ganglion cell ON discharges to become more transient (Frumkes et al., 1995; Zhang et al., 1997), an effect seen in ON bipolar cells (Zhang et al., 1997). Zhang et al suggest a serial synaptic pathway to explain this counterintuitive result. On this model, the native action of GABA, not GABA antagonists, is to make light responses more transient, through delayed inhibition. Amacrine cells synapsing on bipolar cells with GABAC synapses, however, are themselves inhibited by other amacrine cells utilizing GABAA synapses. Blockade of the latter input causes more robust inhibition of bipolar terminals by GABAC and further transience of light responses. GABA release from amacrine cells activates receptors on bipolar cell terminals, causing the suppression of a depolarization-elicited calcium current (Maguire et al., 1989; Matthews et al., 1994) and associated synaptic release (Mack et al., 2000) presumably modulating or reducing neurotransmitter release from these cells (Pang et al., 2002). GABA action appears stronger in ON responses (Zhang and Slaughter, 1995).
Glycine applied to bipolar cells elicits a strychnine-sensitive, hyperpolarizing chloride current. As with GABA, different regions of bipolar cells are differentially sensitive to glycine. In mouse (Suzuki et al., 1990; Kaneko et al., 1991) and carp (Kondo and Toyoda, 1983) the axon terminal shows the greatest sensitivity; while in rat (Karschin and Wassle, 1990) and salamander (Maple and Wu, 1998) the dendrites are more sensitive. There is a tendency for glycinergic inhibitory circuitry to impinge selectively on OFF cone bipolar cells (Cunningham and Miller, 1980; Kondo and Toyoda, 1983); the outstanding example is AIIamacrine innervation of the mammalian OFF bipolar cells and OFF ganglion cells (Kolb, 1979; Pourcho and Goebel, 1985; Wässle et al., 1986; Müller et al., 1988), in this case mediating dark adapted center responses. Noise analysis performed on glycine-elicited currents from dendrites and axon terminal suggests that each region may express a different subtype of glycine receptor (Du and Yang, 2002). In fish retinas glycinergic inputs to bipolar-cell dendrites and axon terminals are believed to arise directly from populations of amacrine and glycinergic interplexiform cells (Maple and Wu, 1998). Glycine-containing interplexiform cells have only been seen so far in fish retinas; glycine receptors can be found on processes postsynaptic to photoreceptors, including bipolar cell dendritic processes (Smiley and Yazulla, 1990).
Glycine is believed to modulate the surround light responses of bipolar cells, though the reported effects of glycine are not consistent. Stone and Schutte (1991), working in Xenopus, report that glycine application eliminated surround responses in both ON- and OFF-type bipolar cells. In contrast, surround responses in salamander are not blocked by glycine (Hare and Owen, 1996). While GABA application elicits responses in all bipolar cells examined, glycine elicits responses from only a subset of bipolar cells, such as OFF bipolars in carp (Kondo and Toyoda, 1983) and the small-field bipolar cells in skate (Qian et al., 2001), suggesting glycine may have a selective role in retina. Glycinergic feedback connections between amacrine and bipolar cells decrease light-evoked glutamate release onto ganglion cell dendrites (Pang et al., 2002). Glycinergic feed forward synapses transfer rod bipolar signals from AII amacrine cells to OFF cone bipolar terminals in mammalian retinas (Kolb, 1979; Merighi et al., 1996). Thus, glycinergic synapses onto bipolar cells may be important in mediating the transfer of information among neurons in both the proximal and distal retina.
Neurotransmitter release from bipolar cell axon terminals
Due to their large size, the axon terminals of goldfish Mb1-type ON-bipolar cells are used as a model system in which to examine neurotransmitter release. The axon terminal can be directly recorded in patch clamp studies (von Gersdorff et al., 1996). Changes in internal calcium (Lagnado et al., 1996) and both exocytosis and endocytosis activity (Lagnado et al., 1996; Zenisek et al., 2000) can be detected using fluorescent calcium probes and capacitance measurements. Images of releasing vesicles at Mb1 terminals are seen by evanescent fluorescence in figure 20.
Neurotransmitter release from bipolar terminals occurs at ribbon synapses (Dowling and Boycott, 1966; Dowling, 1987); conventional synapses are rare in bipolar axon terminals although they have been seen in some species (see Miller et al., 2001). Each ribbon is an electron dense structure oriented perpendicular to the plasma membrane. One ribbon may contain as many as ~110 tethered vesicles along the sides, and vesicles along the base of the ribbon, or “docked vesicles”, are in contact with the presynaptic membrane (von Gersdorff et al., 1996)(See cartoon in Fig. 21 below). All vesicles associated with the ribbon constitute the readily releasable pool of vesicles. Since one axon terminal averages 55 active zones in the goldfish, each with an associated ribbon (Zenisek et al., 2000), there are ~6000 tethered or rapidly releasable vesicles per terminal (von Gersdorff et al., 1996). Combining these values with capacitance measurements indicates that maximal release per active zone occurs at a rate of ~500 vesicles/sec (von Gersdorff et al., 1996). Species with smaller rod or cone bipolar axon terminals (amphibians, reptiles and mammals) have smaller numbers of ribbons and smaller volumes to contain synaptic vesicles so the release rates may be different compared with the model goldfish system.
The ribbon synapse, in the absence of light, releases vesicles spontaneously. The single spontaneous excitatory postsynaptic synaptic currents (sEPSCs) can be studied by voltage clamp techniques in ganglion cells (Miller et al., 2001). It is thought that normal spontaneous release activates AMPA receptors located immediately below the active release zone (Fig. 21). Light stimulation induces release of many vesicles along a single ribbon site and glutamate spillover activates both AMPA and NMDA receptors (Fig. 21). The patch recordings of sEPSCs, under conditions of hyperosmotic Ringer to enhance rates of spontaneous events, indicate both large and small as well as fast and slow events (Fig. 21, control). The sEPSCs are mostly eliminated by NBQX, a highly selective antagonist for AMPA and kainate receptors (Fig. 21, NBQX). But small amplitude events still are seen (Fig. 21, NBQX) until the NMDA antagonist D-AP7 is added (Fig. 21, NBQX+DAP7). This indicates that both AMPA and NMDA receptors are active in post-syanptic ganglion cells (Gottsman and Miller, 1992). Further, a maintained inward current is also blocked by both these antagonists, suggesting bipolar-cell ribbon synapses transfer information across a broad temporal spectrum.
Vesicular release at the bipolar ribbon synapse occurs in a calcium-dependent manner (Heidelberger et al., 1994; von Gersdorff and Matthews, 1994; Morgans, 2000), though there does not appear to be an absolute requirement for calcium, as other divalent ions, such as strontium and barium, can stimulate exocytosis, though to a lesser degree (Neves et al., 2001). Calcium entry occurs through L-type channels in goldfish (Heidelberger and Matthews, 1992) and/or T-type channels in mouse (Pan et al., 2001). These channels are located on the axon terminal membrane. Internal calcium concentrations of 10-20 mM stimulate exocytosis (Heidelberger et al., 1994) of the readily releasable pool (von Gersdorff et al., 1996; Burrone and Lagnado, 2000; Zenisek et al., 2000). Exocytosis occurs in two phases. Initially, membrane depolarization elicits an increase in capacitance (time constant ~1.5ms) corresponding to the rapid release of docked vesicles. This is followed by a second capacitance increase with a slower time constant (~250-300ms), believed to represent the movement of tethered vesicles to the active zone and their subsequent release (Mennerick and Matthews, 1996; Zenisek et al., 2000). Estimates indicate that 20% or ~1100 vesicles (of the 6000 in the readily releasable pool) are released during rapid exocytosis (Mennerick and Matthews, 1996; Burrone and Lagnado, 2000), with the remainder released during the slow component. The depleted pool is restocked rapidly (time constant ~8s) (von Gersdorff and Matthews, 1997). Both the fast and slow phases are calcium-dependent, though they display differential sensitivities to calcium buffers (Mennerick and Matthews, 1996).
Following neurotransmitter release, the vesicular membrane is recovered rapidly (von Gersdorff and Matthews, 1994) and continuously (Lagnado et al., 1996; Rouze and Schwartz, 1998). The continual cycling of vesicles through the processes of exocytosis and endocytosis, is compatible with tonic release of neurotransmitter (Lagnado et al., 1996). This is suspected as bipolar cells generate sustained responses to light, and at least in some cases, transmit sustained signals to postsynaptic neurons (Werblin and Dowling, 1969). Though neurotransmitter is released following continuous or paired-pulse stimulation of the terminals, release decreases with time (Mennerick and Matthews, 1996; Burrone and Lagnado, 2000). This synaptic depression is believed to be due to depletion of the readily releasable pool and a decrease in exocytosis of this pool (Burrone and Lagnado, 2000).
5. Behavioral and clinical implications of bipolar cell abnormalities
The ON bipolar cell appears uniquely vulnerable. The mGluR6 receptor, for example, can be selectively removed (i.e., knocked out) without major effect on other neural pathways. This can be accomplished through a variety of techniques, such as use of selective pharmacological blocking agents (i.e., APB) or site directed mutagenisis techniques designed to eliminate the mGluR6 receptors themselves. Further, naturally occurring mutations and disease processes unrelated to mGluR6 selectively target ON bipolar cells. Surprisingly humans or animal models with ON-bipolar deficit(s) perform visual tasks relatively normally. The major deficit is loss of nocturnal vision, which appears dependent on the physiological integrity of ON bipolar cells.
Mice with ON bipolar knockout perform visual tasks
The electrophysiological consequences of site-directed mutagenisis directed at the ON pathway are seen in figure 4 for mGluR6 deficient mice. The electroretinographic b-wave component, which arises from the activity of ON bipolar cells, is abolished in the knockouts (Masu et al., 1995)(Fig. 4). Furthermore these authors demonstrate that light-evoked field potentials from the superior colliculus, which in mouse is the main termination site for ganglion cell axons, lack ON responses though OFF-type waves appear. In wild type mice, transient collicular waves are seen at both onset and cessation of light stimuli.
In contrast to the physiological findings, no deficit in visual behavior is readily observed. In a shuttle box avoidance learning analysis, both mutant and wild type mice performed equally well. While mutant mice were capable of performing visual tasks, some visual system alterations were noted. Mutant mice had normal circadian clocks, but the daily activity pattern was different. The normal light-induced reduction in activity was greatly delayed (Takao et al., 2000). Pupillary responses were observed only at high light levels, and optokinetic responses only at high contrasts in mutant mice (Iwakabe et al., 1997), suggesting a general loss of sensitivity. These studies indicate that the OFF bipolar cells alone can mediate vision, even if somewhat impaired. Interestingly the ON and OFF layering of the inner plexiform layer persists in the mutants (Tagawa et al., 1999).
Melanoma-associated retinopathy (MAR)
Some patients with malignant melanomas lose night vision. They may further report hallucinations consisting of shimmering blobs of white light (Ripps, 1982; Berson and Lessell, 1988). Visual processing in daylight appears otherwise normal. Color vision is not affected, nor is visual acuity dramatically worsened. Electroretinography reveals ON bipolar cell deficits for these patients. As with mGluR6 deficient mice, the b-wave is selectively absent in both rod and cone driven responses (Alexander et al., 1992). Although originally thought to be a side effect of chemotherapy (Ripps, 1982), it became clear that the syndrome might arise in patients prior to chemotherapy (Berson and Lessell, 1988; Alexander et al., 1992). The IgG serum fraction of MAR patients induces reversible electroretinographic disturbances similar to MAR when injected into the eyes of monkeys (Lei et al., 2000). Electroretinographic a-waves and d-waves remain, the b-wave is lost from both rod and cone responses (Fig. 22). MAR appears to be caused by an autoimmune attack on retinal ON bipolar cells for rod and cone vision. Antibodies induced by the melanoma cause the visual deficit.
Congenital stationary night blindness (CSNB)
This visual dysfunction is an inherited retinal disease very similar in symptoms to MAR. In the Schubert-Bornschien, or complete, type (Schubert and Bornschein, 1952), there is loss of nocturnal or rod vision (Fig. 23), but in daylight, cone-mediated color vision and visual acuity are relatively normal (Goodman and Bornschein, 1957; Miyake et al., 1986), though the sensitivity of cone vision is somewhat reduced (Miyake et al., 1986). The disease appears to be X-linked, affecting primarily males (Miyake et al., 1986).
Electroretinograms reveal a loss of b-waves for both the rod and cone systems. ON bipolar cell signals appear greatly depressed or absent, OFF cone bipolar signals, as represented by the electroretinographic d-wave, are spared (Alexander et al., 1992), as is the rod a-wave (Goodman and Bornschein, 1957) (Fig. 23). The presence of a rod a-wave but not b-wave provided the first suggestion of a genetic, post receptor, neural processing disease in the retina (Goodman and Bornschein, 1957).
CSNB can be separated into two varieties: complete and incomplete. Genetic analysis reveals that the complete form of CSNB involves defects in the glycoprotein nyctalopin (Bech-Hansen et al., 2000). Mutant proteins may disrupt the development of ON bipolar cells. The genetic defect in incomplete CSNB has been localized to a gene uniquely expressed in retina and similar to the L-type calcium channel alpha subunit (Bech-Hansen et al., 1998). Defects in this gene, CACNA1F, provide an example of a human retinal channelopathy.
6. Visual processing under pharmacological blockade of the ON pathway
The responses of visual neurons in the central nervous system of primates have been investigated under conditions of ON-bipolar blockade using the metabotropic glutamate receptor agonist APB (DL AP-4). Recordings from the dorsal lateral geniculate nucleus (LGNd) indicate that light responses of ON-center geniculate neurons are completely blocked by APB (Schiller, 1982; Schiller, 1984). ON-center geniculate cells are also blocked selectively in rabbit (Knapp and Mistler, 1983).
Recordings of light responses of individual neurons in visual cortex suggest final integration of ON and OFF bipolar-cell signals. Complex cortical cells continue to respond under APB blockade of ON bipolar cells, but leading edge responses to bright squares drifting through the receptive field are lost. (Schiller, 1982). The directional selectivity and orientation selectivity of cortical cells appears unperturbed by the blockade. (Schiller, 1982). In a parallel study, monkeys under APB blockade were found to have much poorer perception of light increments than light decrements, but relatively unimpaired perception of simultaneous spatial contrast (Dolan and Schiller, 1994).
Dim light responses are conveyed by ON bipolar cells
One common feature of rod-dominated mammalian retinas is the emergence of a single, ON-type rod bipolar cell (Dacheux and Raviola, 1986; Yamashita and Wassle, 1991; de la Villa et al., 1995) dominated by the metabotropic, mGluR6, glutamate receptor and associated molecules. Pharmacological blockade of this pathway leads to severe behavioral as well as physiological deficits in night vision. This is true behaviorally for both light increments and decrements (Dolan and Schiller, 1989), as well as for dim light responses in ON or OFF ganglion cells (Müller et al., 1988). Knockout of ON bipolar cell signals in mGluR6-deficient mice leads to loss of light sensitivity evident in the electroretinogram (Masu et al., 1995). As noted above ON bipolar cell diseases in humans are always accompanied by a loss of nocturnal vision. The secondary rod pathways that utilize cone-system OFF bipolar cells appear not to be involved in rod-mediated nocturnal vision, but rather it is rod-bipolar-cell metabotropic receptors that mediate dim light responses.
7. Summary and conclusions.
Bipolar cells are functionally crucial neurons that comprise the middle component of the vertical transduction pathway through the retina. ON- and OFF-type bipolar cells are presynaptic to similarly polarized ganglion cells in the retinal inner plexiform layer and can be distinguished by morphology, light response, and glutamate receptor expression. These cells serve as models in which to examine different aspects of neurobiology, from neurotransmitter release to visual system defects. ON and OFF bipolar cells initiate two functionally independent pathways, the ON and the OFF, each containing center-surround organization, transient and sustained bipolar types, and each capable of image processing. The signals of ON and OFF bipolar cells are relayed separately to higher brain centers. ON bipolar cells appear selectively vulnerable to diseases or pharmacological assault. Loss of ON bipolar cells results in a loss of nocturnal vision.
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