Ординатура / Офтальмология / Английские материалы / Eye, Retina, and Visual System of the Mouse_Chalupa, Williams_2008

Figure 13.3 Tracer coupling pattern of AII amacrine cells in the mouse retina. A, Tracer-coupled group of AII amacrine cell somata following injection of an AII amacrine cell in the wild-type mouse retina. Tracer has moved through AII cell-AII cell gap junctions. B, Plane of focus shifted to the more distal INL to show the tracercoupled somata of ON cone bipolar cells. Tracer has moved through AII cell-ON cone bipolar cell gap junctions as well. Scale bar for A and B = 50 μm. C, No tracer coupling is evident following injection of an AII amacrine cell with Neurobiotin in the Cx36 KO retina. This finding indicates that Cx36 is crucial for both AII cellAII cell and AII cell-ON cone bipolar cell coupling. Scale bar = 10 μm. (A and B, Adopted from Deans et al., 2002, with permission.)

pathways. Taken together, these results indicate that the homologous coupling between AII cells maintains the high sensitivity of signals transmitted by the rod bipolar cells to the inner retina. In the rabbit retina, AII cell coupling is modulated by dopamine (Mills and Massey, 1995) and by changes in adapting background light conditions (Bloomfield et al., 1997), but this has not yet been studied in the mouse.

Scotopic signaling to ganglion cells is also compromised in the Cx36 KO animal, indicating that Cx36 plays a role in the heterologous AII amacrine cell-ON cone bipolar cell gap junctions as well (Guldenagel et al., 2001; Deans et al., 2002). This idea is supported by the finding that tracer coupling between AII amacrine cells and ON cone bipolar cells is disrupted in the Cx36 KO mouse retina (Deans et al.,

Stimulus Intensity (Rh*/rod/s)

Figure 13.4 Intensity-response functions of ganglion cells in the wild-type and Cx36 KO mouse retina. Dashed gray curve indicates the averaged intensity-response function of the high-sensitivity OFF-center ganglion cells in the wild-type mouse retina. These signals are carried by the primary rod pathway. Solid gray line indicates the average intensity-response function of intermediate sensitivity OFF-center ganglion cells in the wild-type mouse retina. The signals are carried by the secondary rod pathway. In the Cx36 KO mouse retina, the intensity-response profile of the high-sensitivity ganglion cells (black curve and data points) is shifted rightward by about one log unit (arrow). Symbols along the abscissa indicate the response thresholds for high-sensitivity cells in the wild-type retina (gray square), intermediate-sensitivity cells in the wild-type retina (gray circle), and high-sensitivity cells in the Cx36 KO retina (black square). (Adapted from Völgyi et al., 2004, with permission.)

2002) (see figure 13.3). Further, glycine accumulation in ON cone bipolar cells derived from diffusion across the gap junction made with AII amacrine cells is eliminated in the Cx36 KO mouse (Deans et al., 2002).

While Cx36 is almost certainly expressed by the AII amacrine cell hemichannel, the composition of the hemichannel on the cone bipolar cell side of the gap junction is less clear. Deans et al. (2002) showed expression of Cx36 reporters in a subset of bipolar cells in a transgenic mouse line (see figure 13.1). These bipolar cells showed axon terminations within sublamina b of the IPL, suggesting that they were ON cone bipolar cells. These data suggested that the AII amacrine cell-cone bipolar cell gap junctions were homotypic, both expressing Cx36. In contrast, Feigenspan et al. (2001) reported that ON cone bipolar cells in the rodent retina did not display Cx36 immunoreactivity, suggesting that the AII cell-cone bipolar cell gap junctions are heterotypic. Further, a study of a conditional Cx45 KO mouse showed that deletion of Cx45 resulted in a reduction of the b-wave of the scotopic ERG and elimination of glycine in Cx45-expressing bipolar cells (Maxeiner et al., 2005), similar to that shown in the Cx36 KO mouse retina (Guldenagel et al., 2001; Deans et al., 2002). These data suggested that at least some

of the AII cell-cone bipolar cell gap junctions are heterotypic. A number of recent studies have confirmed that whereas certain ON cone bipolar cells express Cx36, others express Cx45 (Lin et al., 2005; Han and Massey, 2005; Dedek et al., 2006). Thus, the emerging scenario is that certain AII cell-cone bipolar cell gap junctions are homotypic, with both hemichannels expressing Cx36, whereas others are heterotypic, with Cx36 and Cx45 hemichannels. The existence of heterotypic junctions can explain the different conductances and pharmacology of the AII cell-AII cell and AII cell-cone bipolar cell gap junctions, as well as the rectifying properties of the latter (Mills and Massey, 2000; Veruki and Hartveit, 2002).

Why would different ON cone bipolar cells use different connexins for the gap junctions they form with the AII amacrine cells? Gap junctions assembled from different subunits express different biophysical properties, including gating, permeability, and conductance (reviewed by Bennett and Zukin, 2004). Clearly, the different gap junctions formed between AII cells and cone bipolar cells introduce an additional complexity in the transmission and modulation of signaling in the primary rod pathway. In this regard, it is interesting to note that whereas rod signals are passed from AII amacrine cells to cone bipolar cells under dark-adapted conditions, the direction of signal flow is reversed under light-adapted conditions during which cone signals move into the network of coupled AII cells (Xin and Bloomfield, 1999a). Perhaps the different connexin makeup of AII cellcone bipolar cell gap junctions are related to their dualistic function related to scotopic and photopic vision.

Ganglion cell coupling

Perhaps the most unexpected result of recent studies on tracer coupling in the retina has been the extensive homologous and heterologous coupling patterns seen for ganglion cells in the proximal retina (Vaney, 1991, 1994; Xin and Bloomfield, 1997). At first glance, this extensive coupling appeared problematic, as it suggested lateral intercellular propagation of signals across the IPL, which would result in the reduction of visual acuity of neuronal signals just as they exit the retina. However, a study in the rabbit retina showed that the RFs of ganglion cells approximated the extent of their dendritic arbors, irrespective of the extent of tracer coupling (Bloomfield and Xin, 1997). Further, the tracer-coupling networks formed by ganglion cells with their ganglion and/or amacrine cell neighbors were highly circumscribed, in that coupled cells were usually within one gap junction of the injected neuron. Overall, these findings indicated that ganglion cell gap junctions underlie local operations rather than lateral transmission of signals across the inner retina. Clearly, ganglion cell coupling is not analogous to the electrical syncytia formed by horizontal cells in the outer retina.

Although the core of our knowledge about ganglion cell gap junctions comes from studies of rabbit and cat retinas (Vaney, 1991, 1994; Xin and Bloomfield, 1997), a number of recent studies have extended work to the mouse. Although only a few mouse ganglion cell subtypes have been studied so far, they each display stereotypic tracer coupling patterns. For example, the ON alpha subtype of ganglion cell displays tracer coupling to two populations of amacrine cells with somata displaced to the ganglion cells layer, whereas OFF alpha ganglion cells are coupled homologously to one another and heterologously to two to three subtypes of amacrine cells with somata lying in the INL (Schubert et al., 2005a; Völgyi et al., 2005) (figure 13.5A and D). Reconstruction of the tracer-coupled amacrine cells indicated that they displayed extensive dendritic arbors characteristic of widefield amacrine cell morphology (Völgyi et al., 2005). In addition, Schubert et al. (2005b) found that two subtypes of bistratified ganglion cells in the mouse retina, including ONOFF direction-selective cells, are homologously coupled to their neighbors (figure 13.5G). A number of other ganglion cell subtypes in the mouse also show characteristic tracer coupling (figure 13.5I–L), suggesting that electrical synaptic transmission is common to the microcircuitry in the inner retina and thereby likely plays a major role in shaping ganglion cell light responses.

Relatively little is known about the connexin makeup of murine ganglion cell gap junctions. Recent studies have shown that heterologous gap junctions formed between amacrine cells and both ON and OFF alpha ganglion cells are dependent on Cx36 in that tracer coupling is abolished in the Cx36 KO mouse retina (Schubert et al., 2005a; Völgyi et al., 2005) (see figure 13.4A–E). However, the subunit composition of the homologous gap junctions connecting alpha ganglion cells is less clear. Völgyi et al. (2005) found that alpha cell-alpha ganglion cell tracer coupling remains intact in the Cx36 KO mouse retina, whereas Schubert et al. (2005a) reported that it is abolished in their Cx36 KO strain. This discrepancy may be explained either by divergent phenotypes of the two mutant mouse strains or by the different histological methods employed by the two research groups. In any event, these conflicting data highlight the problems that may occur in interpreting data from mutant mouse models and stress that caution must be taken in drawing conclusions.

Most recently, Cx45 has emerged as a possible constituent of ganglion cell gap junctions (Petrasch-Parwez et al., 2004). So far, immunolabeled Cx45 puncta have been localized to the homologous gap junctions connecting neighboring ON-OFF direction-selective ganglion cells (Schubert et al., 2005b) (see figure 13.4G–H). However, as both Cx36 and Cx45 puncta are widely distributed in the IPL of the mouse retina, it is likely that many other ganglion cell subtypes express these connexins as well. In addition, other yet

Figure 13.5 Tracer and electrical coupling of ganglion cells in the mouse retina. A, Photomicrograph of a Neurobiotin-labeled ON alpha ganglion cell in the wild-type mouse retina. This ON alpha cell is surrounded by a halo of tracer-coupled small (open triangle) and large, darkly labeled (arrow) amacrine cell somata. B, Neurobiotin-labeled ON alpha ganglion cell in the Cx36 KO mouse retina is tracer coupled only to small amacrine cells. C, Cross-correlogram of spontaneous spiking of a pair of neighboring ON alpha ganglion cells in the wild-type mouse retina shows a prominent central peak characteristic of unimodal spike synchrony. Line indicates 99% confidence limit. D, Photomicrograph of a Neurobiotin-labeled OFF alpha ganglion cell in the wild-type mouse retina. The OFF alpha cell is coupled both homologously to nearest neighbors and heterologously to two to three subtypes of amacrine cells (arrow). E, Neurobiotin-labeled OFF alpha gan-

glion cell in the Cx36 KO mouse retina reveals the loss of tracer coupling to amacrine cells. F, Cross-correlogram of a pair of OFF alpha ganglion cells in the wild-type retina shows two prominent peaks with short latency, which is a characteristic of bimodal spike correlation due to direct ganglion-to-ganglion cell coupling. G, Tracer coupling pattern of a Neurobiotin-labeled ON-OFF direction selective ganglion cell in the wild-type mouse retina. This cell displays homologous coupling to its nearest neighbor ganglion cells. H, Neurobiotin-labeled ON-OFF direction selective ganglion cell in the Cx45 KO retina shows no evidence of tracer coupling. I–L, Photomicrographs showing the tracer coupling pattern of a variety of ganglion cell subtypes injected with Neurobiotin. All these cells show heterologous coupling to amacrine cells. Scale bar = 100 μm for A–H and 150 μm for I–L. (G and H, Adapted from Schubert et al., 2005b, with permission.)

undiscovered connexins will likely be added to this list in the future. In a recent study, Dvoriantchikova et al. (2006) showed that pannexin 1 and 2 (Panx1, Panx2), two members of the pannexin protein family, are abundantly expressed by retinal neurons, including ganglion cells. This suggests that besides connexins, pannexin proteins may also constitute ganglion cell gap junctions in the mouse retina. The role of pannexins in retinal signal processing is unknown and will no doubt be an important aim of future research.

Functional role of ganglion cell coupling

Ganglion cells appear to couple in restricted groups, thereby preventing significant lateral spread of signals and maintaining spatial acuity. Thus, the gap junctions formed between ganglion cells appear to underlie local signal processing rather than global integration exemplified by the horizontal cells. It has been hypothesized that ganglion cell coupling underlies coherent firing of ganglion cell neighbors, ranging from broad correlations spanning tens of milliseconds to finely tuned spike synchrony with 1–3 ms latencies (Mastronarde, 1983; Meister et al., 1995; Brivanlou et al., 1998; DeVries, 1999; Hu and Bloomfield, 2003). Concerted firing accounts for up to one-half of retinal spike activity, suggesting that electrical coupling plays an important role in encoding visual information (Castelo-Branco et al., 1998; Schnitzer and Meister, 2003).

Direct ganglion cell to ganglion cell coupling is thought to mediate a fast (<2 ms) and reciprocal excitation that is reflected by prominent dual peaks in cross-correlograms of simultaneously recorded ganglion cell neighbors. This idea is supported by simultaneous recordings from homologously coupled OFF alpha ganglion cell pairs in the mouse retina, which produce bimodal, narrow spike correlations (figure 13.5F ). In contrast, cross-correlograms of neighboring ON alpha ganglion cells, which are coupled only indirectly through amacrine cells, display a narrow, unimodal profile (figure 13.5C). This correlation profile for ON alpha cell neighbors likely reflects electrical synaptic inputs from common amacrine cells that give rise to synchronous spikes. These findings support the idea that homologous and heterologous coupling produce different types of correlated activity in neighboring ganglion cells (Brivanlou et al., 1998; DeVries, 1999; Hu and Bloomfield, 2003).

Finally, intercellular communication via gap junctions plays an important role in the development of neuronal circuits, including cell differentiation and pathfinding (Naus and Bani-Yaghoub, 1998). Ganglion cell gap junctions are thought to play a critical role in regulating the spontaneous activity, seen as spontaneous waves of depolarization, in developing retina that plays a role in refining retinalthalamic and intraretinal connections (Sernagor et al., 2001; Grubb and Thompson, 2004). Bath application of gap

junction blockers results in a reduction in the size and frequency of retinal waves (Singer et al., 2001; Syed et al., 2004). In a Cx36 KO mouse, Hansen et al. (2005) showed that Cx36 gap junctions play a critical role in suppressing ganglion cell firing between retinal waves during postnatal development. Thus, retinal gap junctions play an important role in the normal development of the visual system.

Conclusion

It is now abundantly clear that electrical coupling via gap junctions is ubiquitous in the vertebrate retina. Not only are gap junctions and their subunit connexin proteins widely expressed in both plexiform layers, but converging evidence suggests that they are expressed by most of the approximate 60 subtypes of retinal neurons. The finding that gap junctional conductances are affected by neuromodulators and changes in light adaptation indicates that electrical synaptic transmission forms a complex and dynamic mode of cellular communication. Although we are just beginning to elucidate the types of connexins (and pannexins) expressed in the retina, it is already clear that gap junctions play a wide variety of integrative functions, including (1) reducing the signal-to-noise ratio of the cellular responses of cones and amacrine cells, (2) synchronizing the spike activity of neighboring ganglion cells, (3) providing for interactions between the rod and cone pathways, (4) creating a secondary rod pathway, and (5) forming a syncytium of horizontal cells that signals ambient background illumination important for contrast signaling.

The retina is arguably the best model system in which to study the role of electrical synaptic transmission in the CNS. With the recent generation of mutant reporter and connexin KO models, the mouse has become the premier subject to study gap junctions in the retina. Future studies using cellspecific and inducible connexin KO mice models should be able to address the contribution of particular neuronal gap junctions to visual signaling. Determining the distribution and regulation of gap junction is an important challenge to understanding the functional roles of electrical coupling in the retina and their relationship to chemically mediated synaptic transmission. The mouse retina is expected to remain a vital resource in meeting this challenge.

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Vision is initiated in rod and cone photoreceptors when light is transduced into an electrical signal. Much of our understanding of the general synaptic function of the retina has come from in vitro and in vivo studies of the salamander, cat, rabbit, and primate (Rodieck and Brening, 1983; Dowling, 1987). These elegant studies have provided a general framework of synaptic transmission (figure 14.1) that includes the vertical pathway of excitatory neurotransmission, beginning with photoreceptor (rod or cone) input to bipolar cells (BCs), followed by either a direct input from BCs to retinal ganglion cells (RGCs) or an indirect input to RGCs from BCs via an intermediary amacrine cell. In addition, lateral inhibitory pathways modulate the excitatory signaling in the vertical pathway. First, lateral inhibition occurs in the outer plexiform layer (OPL) via feedback from horizontal cells at the photoreceptor to BC synapse (Baylor et al., 1971; Shelley et al., 2006). In the inner plexiform layer (IPL), amacrine cells mediate lateral inhibition via feedback, feedforward, and serial inhibition (Cook and McReynolds, 1998; Werblin et al., 2001). Finally, there are other pathways that modulate retinal function, including dopaminergic control of light adaptation (Weiler et al., 2000), gap junctions (see chapter 13, this volume) and d- serine (Miller, 2004).

Because the morphological plan of the murine retina, described in chapter 12, is very similar to the structure of the retina in other mammalian species, it is likely that the basic function of the vertical and lateral pathways is also similar. Throughout this chapter, then, we compare the findings obtained in the murine model with those obtained in other mammalian and vertebrate models. With the advent of transgenic and knockout technology, the mouse has rapidly become an important model in which to explore the basic functional blueprint provided by earlier studies and begin to analyze the workings of the retina on a gene-by- gene basis.

This review focuses primarily on work conducted in murine mutants, both natural and induced, and in transgenics to elucidate the control of (1) excitatory synaptic transmission from the photoreceptors to the BCs in the OPL, (2) the depolarizing BC (DBC) signaling pathway, and (3) the control of feedback inhibition that shapes synaptic transmis-

sion from BCs to RGCs. The integration of these systems is manifested in the visual response properties of RGCs, which provide the basic interface between the visual environment and the rest of the CNS. Electrical communication among retinal neurons via gap junctions is a critical aspect of the modulation of synaptic transmission in the retina; because this topic is covered in chapter 13, it is not considered here.

Synaptic transmission in the outer retina

In the mouse retina, 97% of photoreceptors are rods and the remainder are cones. Although the mouse retina does not have a specialized area, such as the fovea, area centralis, or visual streak as in other mammals, there seem to be few other significant differences in the function of murine rods and cones. Rod photoreceptors are more sensitive and thus function under dark-adapted conditions and low light levels, and their responses saturate at higher light levels. Cone photoreceptors are less sensitive and function under lightadapted conditions. Rod and cone photoreceptor signaling is unique from almost every other neuron in the CNS. In the absence of light, the photoreceptors continuously release the excitatory neurotransmitter glutamate. A light stimulus results in hyperpolarization of the photoreceptor by a wellunderstood signal transduction cascade (for a review, see Calvert et al., 2006) that decreases intracellular cyclic guanosine monophosphate (cGMP) and closes a cGMP-gated cation channel on the photoreceptor outer segments. This causes the photoreceptor to hyperpolarize, which results in a decrease in the release of glutamate from its terminal in the OPL. Both rod and cone photoreceptors follow this general plan, although many of the molecules that function within the G protein cascades differ for each type of photoreceptor. Analysis of the molecular components of the phototransduction cascade has been aided by both their high molar concentrations and the large number of diseasecausing mutations that have been identified (Chen, 2005). As for most neurons in the CNS, release of neurotransmitter from the photoreceptors is dependent on voltage-dependent calcium channels. However, unlike with most other neurons, the release of glutamate from the photoreceptors is graded,

Figure 14.1 Schematic representation of the retinal circuit, showing the pattern of expression of the proteins that contribute to aspects of synaptic transmission discussed in this chapter. A, Overview of the retinal circuit. AC, amacrine cell; BC, bipolar cell; C, cone photoreceptor; GCL, ganglion cell layer; HC, horizontal cell; INL, inner nuclear layer; IPL, inner plexiform layer; NFL, nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; OS/IS outer and inner segments of the photoreceptors; R, rod photoreceptor; RGC, retinal ganglion cell. B, Detailed view of a cone pedicle (B1) and a rod spherule (B2) with their invaginating contacts from depolarizing bipolar cells and horizontal cells and their flat contacts from hyperpolarizing bipolar cells. Also included are most of the preand postsynaptic proteins expressed at this first synapse in the retina that are discussed in this chapter. Also shown is a detailed view of the hypothesized structure of a voltagedependent calcium channel with the α1F subunit forming the pore of this channel (B3). CaBP4, calcium-binding protein 4; Gαo, G protein αo; mGluR6, metabotropic glutamate receptor type 6; nyc, nyctalopin; VDCC, voltage-dependent Ca2+ channel. C, Detailed view of the axon terminals of bipolar cells in the inner plexiform layer. DBC, depolarizing bipolar cell; GABA, γ-aminobutyric acid; HBC, hyperpolarizing bipolar cell. (Adapted from Wässle, 2004, by permission of Macmillan Publishers Ltd.)

and this results in graded potentials in second-order neurons, the bipolar and horizontal cells.

In the dark, photoreceptors are relatively depolarized (resting potential of −40 mV; Schneeweis and Schnapf, 1999) and release glutamate continuously. This high rate of release is thought to be possible because of a unique synaptic spe-

Figure 14.2 Dark-adapted ERGs from control and various preand postsynaptic mutants, with no b-wave (nob) phenotypes show some similarities and some differences. A C57Bl/6J (wild-type) mouse ERG response is shown at the top, and ERGs from various nob mutants are shown. The Nyxnob mouse retina lacks expression of nyctalopin, a protein expressed on DBC dendrites. The Cacna1f nob2 mouse retina lacks expression of the pore-forming voltage-de- pendent calcium channel subunit α1F, expressed in photoreceptor terminals. The double mutant Cacna1f nob2/Cacna1dtm1Jst lacks expression of both the α1F and α1D subunit of the voltage-depen- dent calcium channel, and its response is the same as that from Cacna1f nob2. The Grm6 nob4 mouse mutant lacks expression of mGluR6 on DBC dendrites. All mutants have a normal a-wave and share the absence of a b-wave. It should be noted that there are subtle differences in the residual responses. Scale bar = 100 ms and 500 μV.

cialization, the synaptic ribbon, present in both rod and cone terminals. This structure is thought to enable the continuous release of neurotransmitter by acting in a conveyer beltlike manner, shuttling synaptic vesicles from the readily releasable pool to the active zone. Synaptic ribbons also are present in BC axon terminals and in the terminals of the hair cells in the cochlea, which also utilize graded potentials and where synaptic release of glutamate is continuous.

Mouse mutants of synaptic transmission in the outer retina

Photoreceptors make contact with two classes of BCs, hyperpolarizing bipolar cells (HBCs) and DBCs, which hyperpolarize or depolarize in response to reduced glutamate release (caused by a light stimulus), respectively. The activity of DBCs can be assessed noninvasively by the electroretinogram (ERG), a gross potential reflecting retinal activity to a light stimulus, recorded at the corneal surface. The wild-type (WT) murine ERG waveform, like that of most other vertebrates, has two major components relevant to synaptic transmission in the mouse retina, a- and b-waves (figure 14.2). The a-wave is the early negative-going wave that represents hyperpolarization of the photoreceptors in response to a light flash. Under dark-adapted conditions, this reflects the signal initiated in the rod photoreceptors, while under lightadapted conditions it reflects a cone photoreceptor–initiated

response. The b-wave is derived from depolarization of DBCs, which may be rod or cone DBCs, depending on the adaptation condition of the retina (Robson and Frishman, 1998; Sharma et al., 2005). The ERG has been instrumental in identifying and characterizing spontaneous or genetically manipulated mice with defects in retinal signaling. In addition to being used to identify a host of mouse mutants with a-wave defects that have helped define the rod and cone opsin transduction cascades, the ERG has been used to identify mice that share another functional phenotype: a normal a-wave with an absent or greatly reduced b-wave in their darkor light-adapted ERG. These mutants, collectively called no b-wave, or nob, have a human disease counterpart known as congenital stationary night blindness (Candille et al., 1999; Chang et al., 2006). The presence of a normal ERG a-wave indicates normal phototransduction and an absence of photoreceptor degeneration. The absent or diminished ERG b-wave indicates a defect in synaptic transmission between the photoreceptors and the DBCs.

The first spontaneous mouse mutant described with this functional phenotype was named no b-wave (nob; Pardue et al., 1998). Subsequent no b-wave mutants have been assigned the same nomenclature and numbered according to the chronology of their discovery (nob, nob2, nob3, nob4). Once the mutant genes were identified, and to enhance clarity, the official nomenclature now incorporates the gene name and the allele name (phenotype) for each mutant (see figure 14.1B2 for the expression pattern of each protein, and table 14.1 for nomenclature). Because this ERG phenotype reflects a lack of synaptic activation of second-order DBCs by photoreceptors, mice with both presynaptic and postsynaptic mutations have been discovered. Mouse (and human) mutants with this functional phenotype fall into two groups:

those with presynaptic mutations, involving genes expressed in photoreceptor terminals, and those with postsynaptic mutations, involving genes expressed in DBCs. Generally, mutations in postsynaptic genes have a more severe ERG phenotype and are referred to as complete congenital stationary night blindness. Presynaptic mutants retain a small ERG b-wave and are referred to as exhibiting incomplete congenital stationary night blindness. These mutant models have extended our understanding of the mechanisms that control neurotransmitter release from photoreceptors and the postsynaptic mechanisms that control BC depolarization. In the discussion that follows, we address what has been learned about synaptic transmission at the photoreceptor to BC synapse, within the DBC transduction cascade, and finally how these alterations affect the visual response properties of the RGCs in these models.

Presynaptic Mouse Mutants: Ca2+ and the Control of Neurotransmitter Release from Photoreceptors

Glutamate release from photoreceptors is mediated by Ca2+ influx through voltage-dependent calcium channels, which are heteromultimeric proteins (see figure 14.1B3) consisting of an α1 subunit that forms the pore of the Ca2+ channel and auxiliary β and α2δ subunits that modulate the Ca2+ current, regulate channel activation and inactivation, and, finally, control the proper assembly of the channel and its localization to the membrane (Catteral, 2000). Immunohistochemical data show that rod and cone photoreceptors express l-type voltage-dependent calcium channels, comprised of α1F and α1D subunits in cones and α1F only in rods (Morgans et al., 2005). Although these two subunits result in channels with similar biophysical and pharmacological properties, their absence results in dramatically different functional outcomes.