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

Knockout and natural mutants of the α1F subunit show a significantly reduced ERG b-wave under both lightand dark-adapted conditions, indicating that this subunit is utilized at both rod and cone photoreceptor terminals (Mansergh et al., 2005; Chang et al., 2006). The knockout of the α1D subunit alone has little impact on the ERG b-wave (Wu et al., 2007). To investigate whether the residual lightadapted ERG b-wave in α1F mutant mice might be due to the α1D subunit, the ERG response in double mutants was characterized. The dark-adapted ERG of the α1F/α1D double mutant shows no significant difference from that of the single α1F mutant (see figure 14.2). Therefore, the source of the residual ERG b-wave in α1F mice is more complicated than initially anticipated and may involve other mechanisms, including voltage-dependent calcium channels with other α1 subunits. In addition to mutations in α1 subunits, loss of either the β2 or α2/δ4 voltage-dependent calcium channel subunits also disrupts synaptic transmission (Ball et al., 2002; Wycisk et al., 2006). Further, the same phenotype and thus the same disruption in synaptic transmission in the OPL occur in mice with mutations in a component of the ribbon synapse, Bassoon (Dick et al., 2003), or molecules thought to modulate the voltage-dependent calcium channel CaBP4 (Haeseleer et al., 2004), and extracellular or intracellular matrix molecules (dystrophin: Pillers et al., 1999; Rs1h: Johnson et al., 2006) at the photoreceptor terminal.

In addition to the ERG phenotype, all these presynaptic mutants (with the exception of Cacna1d) share a morphological phenotype. The OPL thins and its synaptic architecture is disrupted. In all cases, the synaptic ribbons in the rod photoreceptors are disrupted, and the dendrites of horizontal cells and the rod BCs extend into the outer nuclear layer; in some cases ectopic synapses appear to form with photoreceptors (Dick et al., 2003; Chang et al., 2006; Bayley and Morgans, 2007).

Postsynaptic Mouse Mutants: Control of the Depolarizing Bipolar mGluR6 Signaling Cascade Synaptic transmission also requires detection of the changes in concentration of neurotransmitter in the synaptic cleft by the postsynaptic cells. Rod photoreceptors contact a single type of DBC (the rod DBC), while cones contact both DBCs and HBCs. The two classes of cone BCs can be distinguished by their response to the change in glutamate release following light activation of photoreceptors. HBCs use an ionotropic AMPA/kainate glutamate receptor that maintains electrical polarity (Saito and Kaneko, 1983, DeVries, 2000); for example, a hyperpolarization in the photoreceptor is matched by a hyperpolarization in HBCs. In contrast, DBCs employ a metabotropic glutamate receptor type 6 (mGluR6) mechanism (Nakajima et al., 1993), which switches the polarity of the response (from hyperpolarization in the

photoreceptors to depolarization in these BCs) by opening a nonspecific cation conductance in response to the decrease in photoreceptor glutamate release (Slaughter and Miller, 1981).

Analysis of the molecular components involved in the DBC signal transduction cascade downstream of mGluR6 remains relatively incomplete (for a review, see Duvoisin et al., 2005). At this time, four mutant mouse models have been reported that disrupt signaling in DBCs. Two disrupt the mGluR itself (Grm6Tm1Nak: Masu et al., 1995; Grm6nob4: Pinto et al., 2007). Given their ERG phenotype, the other two, Gαo (Gnao1tm1Lbi: Dhingra et al., 2000, 2002) and nyctalopin (Nyxnob: Gregg et al., 2003), also must disrupt important components of the DBC signaling cascade. Again, ERG phenotypic screening has been crucial to the identification of two of these mutants (Gregg et al., 2003; Pinto et al., 2007) and to the characterization of the two knockout lines (Masu et al., 1995; Dhingra et al., 2000, 2002). All share the same ERG phenotype, a normal ERG a-wave, (photoreceptor response), and absence of the ERG b-wave (DBC) response (see figure 14.2). In fact, ERG characterization of the Grm6Tm1Nak mouse verified that this receptor was responsible for the DBC component of the ERG b-wave (Masu et al., 1995). The absence of a b-wave in Gnao1tm1Lbi (Valenzuela et al., 1997; Jiang et al., 1998; Dhingra et al., 2000, 2002), along with its postsynaptic expression in all DBCs, provided convincing evidence that this G protein subunit is a component of the DBC signal transduction cascade. Finally, in addition to its functional ERG phenotype, two other lines of evidence clearly place nyctalopin as an integral protein in DBC signaling. First, it is the only one of these models in which the absence of a DBC response to exogenous agonist (glutamate) administration has been verified (figure 14.3; Gregg et al., 2007). Second, a transgenic approach that expressed an EYFP-nyctalopin fusion protein only on the dendritic terminals of BCs produced a functional rescue of both the ERG b-wave (figure 14.4; Gregg et al., 2007) and other downstream visual (RGC) and anatomical defects (RGC axon terminals in the LGN) (Demas et al., 2006). While Gαo and nyctalopin are now established as elements critical to the function of the DBC signaling cascade, their exact roles and positions in this pathway remain a mystery, as does the identity of the nonspecific cation channel that is modulated in response to glutamate changes in the synaptic cleft.

In contrast to the mutant models of presynaptic neurotransmitter control described in the preceding section, retinal structure is normal at the light microscopic level in all four postsynaptic mutants (Grm6Tm1Nak: Masu et al., 1995; Tagawa et al., 1999; Grm6 nob4: Pinto et al., 2007; Gnao1tm1Lbi: Dhingra et al., 2000; and Nyxnob: Pardue et al., 1998; Ball et al., 2003). In Nyxnob and Gnao1tm1Lbi mice, the only models studied at the electron microscopy level, both preand postsynaptic struc-

Figure 14.3 DBCs in Nyxnob mouse retinal slices do not respond to exogenous application of the agonist glutamate. In WT mice, puffs of glutamate directed onto BC dendrites elicit robust outward currents in rod and cone DBCs and inward currents in HBCs. In Nyxnob mice, HBC responses are identical to those in WT mice. In contrast, no response could be elicited in any DBC in Nyxnob retina. The bar above each current trace indicates the glutamate puff duration (100 ms). (Adapted from Gregg et al., 2007.)

tures in the OPL are normal (Dhingra et al., 2000; Pardue et al., 2001). Finally, we know that nyctalopin expression is not required for expression of these other proteins, because its absence does not eliminate expression of either mGluR6 or Gαo (Ball et al., 2003).

Altered outer retina neurotransmission results in complex retinal ganglion cell phenotypes

The impact of these outer retinal defects on the retinal output has been explored by assessing the changes in the visual response properties of mutant RGCs relative to WT RGC function. These downstream effects represent the integration of the individual components of the retinal circuit by the RGCs. Both in vivo and in vitro studies have characterized the light-evoked responses of RGCs in Cacna1f nob2, Grm6 nob4, and Nyxnob mice. In vitro, RGC responses have been studied directly using multielectrode arrays (Demas et al., 2006; Renteria et al., 2006; Pinto et al., 2007) or indirectly analyzed by examining the visually evoked responses in the superior colliculus (SC), a structure that receives direct RGC synaptic input (Sugihara et al., 1997; Mansergh et al., 2005). In vivo, RGC responses have been evaluated using extracellular recording of the spiking activity of individual RGC axons. A broad generality can be made at this time: mutants with presynaptic defects have RGCs whose receptive fields (RFs) can be categorized as responding to either the onset (ON) or the offset (OFF) of a light stimulus. In contrast, mutants with postsynaptic defects that differentially affect

Figure 14.4 Expression of an EYFP : nyctalopin rescue transgene in BCs restores the b-wave component of the ERG in Nyxnob mice. The transgene construct consisted of an 11-Kb fragment from the GABAC ρ1 gene, which drives expression of a murine nyctalopin cDNA with EYFP inserted after amino acid 19. A, Representative dark-adapted ERG waveforms of WT, Nyxnob, and Nyxnob/NyxtgRgg mice at a flash intensity of 1.4 log cd s/m2. B, Light-adapted ERG waveforms of the same WT, Nyxnob, and Nyxnob/Nyxtg mice evoked on a steady rod-adapting background (1.5 log cd/m2) and with a flash intensity of 1.9 log cd s/m2. (Adapted from Gregg et al., 2007.)

the DBC signaling cascade lack normal ON RGC responses, although the effects on OFF RGC responses varies (Demas et al., 2006; Renteria et al., 2006; Pinto et al., 2007).

Retinal ganglion cell responses in mutants with outer plexiform layer presynaptic defects

RGCs responses in Cacna1f nob2 mice, which lack the voltagedependent calcium channel α1F subunit (Cav1.4), are surprisingly normal. At both lightand dark-adapted levels, Cacna1f nob2 RGCs have RFs with center-surround organization that can be classified as ONor OFF-center (figure 14.5) (Chang et al., 2006). The most prominent defect observed under light-adapted conditions is a decrease in the spontaneous activity, along with a compression of the dynamic range of the ON-center Cacna1f nob2 RGCs compared to WT (Chang et al., 2006). The Cacna1f nob2 OFF-center RGCs are indistinguishable from WT OFF-center RGCs. Thus, there appears to be a specific deficit in the ON pathway in this mutant consistent with the reduction in its cone ERG b-wave (Sharma et al., 2005). Although the primary defect in visual processing occurs at the photoreceptor-to-BC synapse, Cacna1f is expressed in the inner retina, and therefore some changes at the level of the RGC could be due to downstream

Figure 14.5 Visual responses of RGCs at lightand dark-adapted levels in Cacna1f nob2 RGCs show similar receptive field (RF) organization to WT controls. The RF organization of ON- (left) and OFF-center (right) RGCs in Cacna1f nob2 (A) and WT mice (B) was assessed with spots of standing contrast whose diameter varied from smaller than the RF center, to matching the RF center, to covering both the RF center and its antagonistic surround. An area response

alterations in IPL synaptic processing. In contrast to these effects, Mansergh et al. (2005) reported a loss of all visually evoked responses in the SC of the Cacna1f tmNtbh knockout mouse, which implies there is no visually evoked activity in either ON or OFF RGCs. Although responses in the SC from Cacna1f nob2 have not been evaluated, a lack of visually evoked activity seems unlikely, given the robust RGC responses in this mutant (Chang et al., 2006). The reason for the differences in these two mutants with apparently identical genetic defects is unclear, as expression of the protein is eliminated in both (Mansergh et al., 2005; Chang et al., 2006). Although the mutations are on different genetic backgrounds (SV129 for the Cacna1f tmNtbh knockout mouse and C57Bl/6J for the Cacna1f nob2 mouse), these phenotypic differences may correspond to the different clinical entities that have been associated with human CACNA1F mutations (congenital stationary night blindness type 2: Bech-Hansen et al., 1998; cone dystrophy: Jalkanen et al., 2006; Aland Island eye disease: Jalkanen et al., 2007).

Another mouse mutant that disrupts neurotransmitter release from photoreceptor terminals is knockout of the β2

function (ARF) was generated for each RGC by plotting the cell’s peak firing rate as a function of spot diameter. At both lightadapted (gray traces) and dark-adapted (black traces) levels, the representative curves show that RGC responses in the Cacna1f nob2 mice are as robust as in WT mice, and their RF organizations are similar.

subunit of voltage-dependent calcium channels, Cacnb2tmRgg. This mutant shares the ERG (Ball et al., 2003) and morphological (Gregg et al., 2008) phenotype characteristic of Cacna1f nob2 mice that lack normal release of glutamate from photoreceptors. Similar to what occurs in Cacna1f nob2, RGCs in Cacnb2tmRgg mice also can be classified as ON and OFF and have a well-defined center-surround RF organization. Again, OFF-center RGC responses are similar to those in WT animals. However, differences in RGC response properties in these two mutants appear at darkadapted levels. Under these conditions, visual responses in Cacnb2tmRgg RGCs are significantly reduced (M. A. McCall, unpublished observations) compared to Cacna1f nob2 and WT RGCs.

The subtlety of the changes in visual processing in the RGCs of these voltage-dependent calcium channel mutants strongly suggests that a scenario in which a single voltagedependent calcium channel subunit combination controls synaptic transmission in rod versus cone photoreceptors is too simplistic. Instead, the differential effects on RF organization and visual responses of RGCs may reflect the pres-

ence of other subunits or the shuffling of subunits in the absence of expression of the primary subunit. There is support for this hypothesis from the characterization of Ca2+ currents in mouse BCs (Berntson et al., 2003). Alternatively, there could be no difference at the level of OPL, but rather alteration in the voltage-dependent calcium channels could occur in the inner retinal circuits (Pan, 2001; Cui et al., 2003; Ma and Pan, 2003), changing neurotransmitter release and synaptic transmission. What is needed now is a strategy in which the voltage-dependent calcium channels are expressed selectively in either the outer or the inner retina, but not both. For example, a transgenic rescue of each photoreceptor voltage-dependent calcium channel phenotype could provide insight into a definitive role for these subunits in outer versus inner retinal synaptic transmission.

Retinal ganglion cell responses in mouse mutants with postsynaptic defects in depolarizing bipolar cell signaling

With the exception of the Nyxnob mouse, the analysis of BC responses has only used the ERG, and thus assessment of outer retinal synaptic function has been restricted to DBC signaling. All four mutants, Grm6 nob4 and Grm6 tm1Nak, Gnao1tm1Lbi, and Nyxnob, share the same functional phenotype, a disruption in signaling that leads to DBC depolarization and b-wave generation. RGC visual response properties have been analyzed in both Grm6 and Nyx mutants. The Gnao1tm1Lbi mutant survives for only a few weeks after birth, complicating in vivo analyses. The RGC phenotype of the spontaneous mGluR6 mutant (Grm6 nob4) and the knockout (Grm6 tm1Nak) are similar and reflect the expected defect in synaptic transmission through the ON pathway (Renteria et al., 2006; Pinto et al., 2007). In both mutants there are spontaneously active RGCs that are not visually responsive, a result never found in WT retinas (Chang et al., 2006; Pinto et al., 2007). Visually responsive RGCs can be classified as ON, OFF, or ON/OFF relative to their response to the onset or offset of a full-field visual stimulus. In the few instances when an ON response could be identified in both Grm6 mutants, its response onset was significantly delayed and its peak firing rate was significantly reduced compared to what is seen in WT animals. In both Grm6 mutants, the characterizations via either multielectrode arrays in vitro (Renteria et al., 2006) or both multielectrode arrays in vitro and extracellular recording in vivo (Pinto et al., 2007) yielded similar results: OFF-center RGCs have RF center-surround organization similar to that of WT cells. The absence of signaling through the ON pathway in the context of normal function in the OFF pathway is consistent with a dysfunction of the mGluR6 receptor, which mediates signaling only in DBCs.

The Nyxnob mouse has the same ERG phenotype as the Grm6 mutants. In addition, Nyxnob DBCs do not respond to exogenous application of agonist, but their HBCs do (see figure 14.3; Gregg et al., 2007). Thus, at the level of the BC, the functional phenotypes should be the same. However, the absence of nyctalopin produces a dramatically different effect on RGC response properties. Although the percentage of visually unresponsive Nyxnob RGCs (Demas et al., 2006) is the same as in Grm6 nob4 (Pinto et al., 2007), none of the Nyx nob RGCs have classic centersurround RF organization (Vessey et al., 2005). Further, the spontaneous activity of the majority of Nyxnob RGCs shows a rhythmic bursting at about 4 Hz (Demas et al., 2006), whereas spontaneous activity in both Grm6 nob4 and WT RGCs is random (Pinto et al., 2007).

One hypothesis to account for this difference between Grm6nob4 and Nyxnob RGCs is that nyctalopin is expressed in the IPL as well as in the OPL (Bayley and Morgans, 2007), whereas mGluR6 is expressed only in the OPL. However, transgenic expression of an EYFP nyctalopin fusion protein only on the tips of DBC dendrites of Nyxnob mice restores not only the ERG b-wave but all spontaneous and visually evoked response properties of Nyxnob RGCs to WT (Demas et al., 2006; Gregg et al., 2007). Thus, another mechanism must underlie these significant differences in downstream visual processing in the Nyxnob mutant that ostensibly shares the same DBC functional phenotype as the Grm6 mutants. If the axon terminals of Nyxnob DBCs are in a constitutively more depolarized state than Grm6 nob4 or Grm6 tm1Nak DBCs, this should alter the release properties of glutamate in the IPL. If this were the case, the mechanism might resemble the following scenario. In the dark in the WT retina, mGluR6 is activated by continuous glutamate release from the photoreceptors, and Gαo is free to modulate the unknown nonspecific cation channel, keeping it in a closed state and the DBC relatively hyperpolarized. Upon light stimulation, photoreceptor glutamate release is reduced, Gαo is sequestered as part of a tripartite G protein/ mGluR6 complex, and the nonspecific cation channel opens, depolarizing the DBC. During the release of Gαo there is an exchange of GDP for GTP, but the exact nature of what controls the cation channel remains unknown. In Grm6 mutants, the absence of mGluR6 expression should allow Gαo to be free to bind GTP and keep the cation channel in a constitutively closed state and the DBC relatively hyperpolarized, consistent with experimental observations (Nawy, 1999). If nyctalopin were required for the closure of the cation channel, then its absence in Nyxnob mice would result in more depolarized DBCs. At this time, there is no empirical evidence for this scenario, and the differences between RGCs in Nyxnob and the Grm6 mutants await an understanding of the function of nyctalopin in this pathway.

Control of the synaptic output of bipolar cells by GABACR-mediated inhibition

Murine BCs have been divided into three functional classes, rod DBCs and cone DB or HBCs (for a review, see Sterling, 1995). Cone photoreceptors contact both cone DB and HBCs, which depolarize in response to increments and decrements of light intensity, respectively (Kolb and Famiglietti, 1974; Nelson et al., 1978, 1981). Cone BCs can be further divided into four types of HBC and five types of DBC, each distinguished by the morphology of their dendritic and axonal terminals, the IPL sublamina within which their axon terminals stratify, and, finally, by protein expression (Ghosh et al., 2004; Pignatelli and Strettoi, 2004). Rod photoreceptors contact a single type of rod DBC that depolarizes in response to a light increment (Bloomfield and Dacheux, 2001; but see Wu et al., 2004). Thus, visual information travels along these two sets of parallel pathways (reviewed by Wässle, 2004). One is segregated in terms of the light levels at which they function, with the rod pathway mediating visual function at low light levels and the cone pathway mediating vision at higher light levels. The second level of segregation occurs within the cone pathway, where cone photoreceptors signal to both DB and HBCs (Murakami et al., 1975). These functional pathways are thought to remain segregated, conveying information about the overall light level (rod and cone) and, within the cone pathway, information about intensity increments and decrements within the visual scene.

The differences in the kinetics of the photoreceptor output to rod and cone BCs have been characterized in other species and found to be temporally distinct. Two mechanisms cause these kinetic differences. First, there are distinct mechanisms of neurotransmitter release that cause synaptic transmission from cones to BCs to be faster than from rods to BCs. Second, there are distinct complements of postsynaptic glutamate receptors that enhance this temporal difference (Schnapf and Copenhagen, 1982; Ashmore and Copenhagen, 1983; Cadetti et al., 2005; Li and DeVries, 2006). While the differences in the kinetics of neurotransmitter release in murine rod and cone photoreceptors have not been thoroughly documented, their BCs utilize the same postsynaptic receptors, mGluR6 on rod and cone DBCs and AMPA/kainate receptors on cone HBCs (Nakanishi et al., 1998; Hack et al., 2001; Snellman and Nawy, 2004). Thus, the murine retina likely follows similar synaptic mechanisms in shaping photoreceptor-to-BC synaptic transmission.

Excitatory responses within the retina are shaped not only by synaptic release kinetics and the complement of postsynaptic glutamate receptors but also by inhibition mediated by GABA and glycine and their receptors (for a review, see Wässle, 2004). The role of inhibition in shaping excitatory transmission in the retina has been recognized for decades

in a variety of species (Dowling, 1987); however, this is a developing area in the mouse, which is aided by our ability to eliminate specific receptor subunits using gene-targeting approaches. The presence of many GABA and glycine receptor subunits expressed in specific patterns within the IPL (Wässle et al., 1998; Haverkamp et al., 2004), as well as kinetic differences and sensitivities to agonists across these receptors, implies important functional differences. To date, the most thorough analyses have been undertaken for the role of the GABAc receptor (GABACR) in shaping both BC and RGC output, because of its restricted expression on BCs, the availability of relatively selective antagonists, and the production of a knockout mouse for the GABACρ1 subunit, which eliminates all GABACRs in the retina (McCall et al., 2002), but see recent work of the Wässle lab (Ivanova et al., 2006; Majumdar et al., 2007; Weiss et al., 2008).

That BC outputs are shaped by presynaptic inhibitory input from GABAergic and glycinergic amacrine cells is well established in a number of species, including mouse (Lukasiewicz and Werblin, 1994; Pan and Lipton, 1995; Dong and Werblin, 1998; Euler and Masland, 2000). In the IPL, this is accomplished by activation of functionally distinct GABAA, GABAC, and glycine receptors on the axon terminals of the BCs (Euler and Wässle, 1998; Shields et al., 2000; Eggers and Lukasiewicz, 2006a, 2006b). Studies using exogenous application of agonists to reveal the types of receptors that mediate inhibitory currents suggest that GABAA, GABAC, and glycine receptor input varies with functional BC class (rod DBC, cone DBC or HBC) (Euler and Wässle, 1998; Shields et al., 2000; Ivanova et al., 2006; Eggers et al., 2007). Because the kinetics of each GABAergic and glycinergic receptor vary, there is the expectation that each provides a distinct modulation of BC output. Exogenous agonist application, however, cannot discriminate among differences in neurotransmitter release, receptor distribution, or circuitry interactions, each of which contributes to how much inhibition is activated from a given receptor when a light stimulus evokes inhibition. Thus, the combined use of stimulus control, receptor antagonists, and, when possible, knockout mice provides a more complete picture of the role of a particular receptor in synaptic transmission. Such an approach has been used to study the role of the GABACR in the control of the synaptic output of BCs and in the visual response properties of RGCs in the retina (McCall et al., 2002; Eggers and Lukasiewicz, 2006a, 2006b; Eggers et al., 2007).

GABACR-mediated inhibition was shown to be important in shaping BC output in several species using an arsenal of pharmacological agents (for a review, see Lukasiewicz et al., 2004). However, the availability of GABACRtmMmc knockout (GABACR) null mice has greatly extended these results in two ways. First, light stimulation has been used to induce inhibitory postsynaptic potentials in the BCs, and second, the

absence of GABACRs throughout the retina permits insight into its role in retinal circuitry both in vitro and in vivo. As with all knockout mice, one must establish that the observed effects of the knockout do not result from secondary effects. For example, is it possible that the absence of gene expression has developmental consequences? For this knockout model, the developmental consequences might include altered expression of other GABAR subunits or the formation of receptors with novel subunit composition, which could have altered kinetics. However, the GABACR null mouse is an example of a well-behaved knockout. The likelihood of developmental alterations is relatively low because it normally is expressed relatively late in development, first detected around postnatal day 6 (Greka et al., 2000), near the time that rhodopsin is expressed and visual signals initiate activity in the retina. Elimination of the expression of the ρ1 subunit of the GABACR, also causes loss of retinal expression of the ρ2 and ρ3 subunits, so that formation of novel GABA receptors is unlikely (McCall et al., 2002).

These aspects have been confirmed functionally by demonstrating that no GABACR-mediated currents could be evoked by either exogenous agonist application (McCall et al., 2002; Eggers et al., 2007) or light stimulation (Eggers et al., 2007). Finally, the GABAAR- and glycine receptor–mediated currents in GABACR null BCs have similar kinetics and overall size as pharmacologically isolated currents in WT BCs (McCall et al., 2002; Eggers et al., 2007). Thus, this knockout fulfills all the necessary criteria to examine its role in synaptic transmission in the inner retina and its downstream effects on retinal processing at the level of the RGCs.

Comparisons of GABAand light-evoked inhibitory currents in WT and GABACR null mice have led to the following conclusions about the role of GABAergic and glycinergic inhibition in shaping the synaptic output of the three BC functional classes in the mouse retina. Glycine and GABAARs shape the peak amplitude, while GABACRs contribute to the time course of rod DBC inhibition (Eggers and Lukasiewicz, 2006a). Across the three functional BC classes, unique combinations of GABAC, GABAA, and glycine receptors contribute to inhibition. Specifically, large, slow, GABAC receptor-mediated inputs dominate rod DBC GABAand light-evoked inhibitory postsynaptic currents (McCall et al., 2002; Eggers and Lukasiewicz, 2006a; Eggers et al., 2007). Slow GABAC and fast GABAA receptor-mediated inputs combine about equally and create inhibitory currents with shorter decays in cone DBCs relative to rod DBCs. Glycinergic inhibition is absent in cone DBCs and contributes relatively little, relative to GABAergic inhibition, in rod DBCs (Ivanova et al., 2006; Eggers et al., 2007). Glycinergic inhibition is most prominent relative to GABAergic input in the inhibitory responses of cone HBCs when the retina is darkadapted, owing to inputs from the AII amacrine cell (Eggers

et al., 2007). Under pharmacological conditions where the AII circuit is inactivated, which may mimic a lightadapted condition, inhibitory input to the cone HBCs is modified and comes directly through the cone pathway. Under these conditions GABAAR inhibition dominates, although a small contribution from GABACRs is present. Thus, unique presynaptic receptor combinations mediate distinct forms of inhibition, which selectively modulate BC outputs across functional classes. This differential inhibitory input could work to enhance distinctions among these parallel retinal signals that are established by differences in the time course of their excitatory inputs that were discussed earlier.

GABACR-mediated feedback inhibition alters the visually and electrically evoked responses of ON-center retinal ganglion cells

Depolarization of BCs opens voltage-dependent calcium channels (Berntson et al., 2003; Awatramani et al., 2005), triggering the release of glutamate from their terminals in the IPL, which is translated into spiking activity in the thirdorder RGCs. Relative to the input of RGCs, GABACR feedback inhibition onto the axon terminal of the BC is considered a form of presynaptic inhibition. Presynaptic inhibition has been shown in a number of systems in both invertebrates and vertebrates to be a critical factor that regulates neurotransmitter release probability (reviewed in MacDermott et al., 1999). In general, neurotransmitter release from a presynaptic neuron stimulates a postsynaptic inhibitory neuron, which feeds back and activates presynaptic inhibitory ionotropic receptors and induces a hyperpolarizing Cl− current in the original output cell. This reduces Ca2+ influx, regulating neurotransmitter release (Dudel and Kuffler, 1961). In the retina, the presynaptic BC axon terminal releases glutamate, which provides an excitatory input to both the RGC and GABAergic amacrine cells. The GABACR on the BC axon terminal detects a reciprocal input from the GABAergic amacrine cell and mediates feedback inhibition. To determine the role of this feedback inhibition in shaping the synaptic output of BCs, the visual response properties of RGCs in GABACR null and WT mice were evaluated using both visually and electrically evoked stimuli. As described in this chapter, presynaptic inhibition mediated by GABACRs differentially shapes inhibition among functional classes of BCs, and this would be expected to shape excitatory transmission between BCs and RGCs. Thus, under light-adapted conditions, ON-center RGCs, which receive direct input from cone DBCs, should be differentially affected compared to OFF-center RGCs when GABACR null and WT responses are compared.

It has been observed that dynamic range and sensitivity differ between ONand OFF-center RGCs (Chichilnisky

and Kalmar, 2002; Zaghloul et al., 2003), but the synaptic mechanisms underlying these effects had not been explored. Differences in the visual response properties of GABACR null and WT RGCs show that this feedback inhibition regulates the ability of the ON-center RGCs to encode light intensity increments and the dynamic range of their light-evoked responses (McCall et al., 2002; Sagdullaev et al., 2006). When the dynamic range was assessed using electrical stimulation of the OPL, a similar difference was noted. WT ON-center RGCs had a wider dynamic range than their counterparts in GABACR null mice. This similarity strongly suggests that the changes observed result from GABACR-mediated control of synaptic transmission from BC to RGC. Consistent with the differential distribution of GABACR-mediated inhibition across functional BC classes, the visual response properties in OFF-center GABACR null and WT RGCs are similar. This implies that GABACR presynaptic inhibition regulates glutamate release from DBCs, but HBC output is not similarly controlled.

There is strong evidence that GABACR input reduces glutamate release from DBCs. In the absence of GABACR expression or in the WT retina when the BC circuit is driven by a very strong stimulus, glutamate release is enhanced, leading to spillover activation of perisynaptic NMDA receptors on ON-center RGCs (Sagdullaev et al., 2006). In addition, we have recently discovered that when stimuli of different luminance contrast are used to stimulate the ONcenter cells, GABACR-mediated inhibition regulates surround inhibition, primarily when contrast is low (figure 14.6; Yarbrough et al., 2008). This difference is consistent with the same underlying mechanism regulating neurotransmitter release and spillover activation in encoding luminance contrast. The GABACR regulation of neurotransmission at the BC-to-RGC synapse extends the dynamic range of the RGCs and enables this synapse to encode a wide range of light intensities and luminance contrasts.

The laboratory mouse is a relatively recent addition to the species used to characterize retinal circuitry. However, it is now clear that the morphology and much of the circuitry of the murine retina are similar to those in other species, including primates, even if mice lack a fovea or area of central retinal specialization. The power of forward and reverse genetics (Pinto and Enroth-Cugell, 2000), combined with gene targeting and transgenic and mutagenic approaches, is unique to the mouse and is greatly extending current knowledge regarding the role of specific molecules in visual function. In this chapter, we have highlighted just two areas where this approach has been fruitful, namely, to begin to analyze the role of signaling across the OPL and to understand the role of one inhibitory receptor in the IPL. These studies already have yielded surprises; no doubt, further surprises await us in the future.

Figure 14.6 WT ON-center RGCs have smaller light-evoked responses throughout the RF than GABACR null RGCs at low but not high luminance contrast. The RF organization of ON-center RGCs in WT and GABACR null cells was assessed using spots of standing contrast (33% or 67%) and varying diameter on a 20cd/m2 background. An ARF was generated for each RGC by plotting the cell’s peak firing rate as a function of spot diameter. Average ARFs for WT and null mice at two different contrasts, 33% (top: WT, n = 39; null, n = 44) and 67% contrast (bottom: WT, n = 35; null, n = 51) show that, at low contrast, WT ON-center RGCs have significantly lower light-evoked responses than null cells across all spot sizes. (Repeated measures ANOVA for WT vs. null at 33%, genotype P < 0.001.) (Adapted from Yarbrough et al., 2008.)

acknowledgments Work was supported by NIH grant nos. EY014701 (MAMc), R24 EY15638 (NSP), and EY12354 (RGG) and by RPB awards to the Departments of Ophthalmology and Visual Science, University of Louisville, and the Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. The authors acknowledge the contributions of their laboratory staff and collaborators whose work is described in this review, in particular Drs. S. L. Ball, E. D. Eggers, M. T. Pardue, B. T. Sagdullaev, K. A. Vessey, and G. L. Yarbrough. The authors especially thank Dr. P. D. Lukasiewicz for his thoughtful comments on this chapter.

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