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AII Amacrine Cells by Mahnoosh Farsaii and Victoria P. Connaughton

 

Mahnoosh Farsaii and Victoria P. Connaughton

 

1. Introduction.

The AII amacrine cell is characterized by a multifaceted connectivity and physiology. It is unique among amacrine cells in that it participates predominantly in the vertical flow of information though the inner retina, contributing to center mechanisms, rather than in lateral inhibitory pathways. As its multilayer stratification, and synaptic partners, suggest, the AII transmits both rod and cone-driven signals within the ON- and OFF- retinal pathways to the inner retina. This chapter summarizes the morphological and physiological characteristics of AII cells focusing on data obtained from four mammalian species: rat, cat, rabbit, and monkey.

2. Morphology and Distribution.

The AII amacrine cell, originally described by Kolb and Famiglietti (1974; Famiglietti & Kolb, 1975) is the most studied amacrine cell of the vertebrate retina. It has been identified in a variety of mammalian retinas. The AII is a narrow-field, bistratified amacrine cell that is involved in synaptic contacts throughout the IPL. Its morphology has been identified using a variety of staining methods, such as Golgi techniques (Fig.1a) (Kolb & Famiglietti, 1974; Famiglietti & Kolb, 1975), Lucifer and HRP labeling of recorded neurons (Nelson, 1982), and fluorescent dyes such as DAPI (4,6-diamidi no-2-phenylindole) or Lucifer Yellow (Vaney, 1985, 1991; Mills & Massey, 1991).

 


Fig. 1a. Golgi stained image of an AII amacrine cell in cat retina.

Fig. 1b. AII amacrine cells immunocytochemically stained with anti-parvalbumen in rodent retina (courtesy Nicolas Cuenca).

More recently, immunocytochemical methods targeting various calcium binding proteins (parvalbumin and calretinin) have been employed to selectively label AII cells in rabbit (Casini et al., 1995; Massey & Mills, 1999) and rodent (Fig. 1b) (Wassle et al., 1993). Primate AII cells are also labeled with calretinin (Wassle et al., 1995; Mills & Massey, 1999 ), though not selectively (Kolb et al., 2002). Regardless of technique used, the AII cell has a consistent morphology (Figure 1a) with a round or oval shaped cell body 8-10um in diameter located in the proximal inner nuclear layer. In peripheral retina, the cell body often extends into the IPL. The distribution of AII cell bodies is non-random, forming a regular mosaic (Vaney, 1985; Mills & Massey, 1991; Kolb et al., 2000). Calculated regularity indices range from 4.0 (inferior retina) to 5.4 (temporal midperipheral retina) in rabbit (Vaney et al., 1991a), cat (Vaney, 1985) and rat (Wassle et al., 1993); a lower value was calculated in monkey (Wassle et al., 1995). AII dendritic trees are reported to be more regularly distributed than their cell bodies, with their processes filling in gaps between adjacent cell bodies to get full coverage of the IPL (Vaney et al., 1991a; Wassle et al., 1995).

The bistratified nature of AII cells arises from two distinct dendritic trees (Figures 1a, b). The dendritic tree in sublamina a (s1 and s2) is composed of short, thin processes ending in lobular appendages that radiate in all directions from typically a single primary dendrite (Famiglietti & Kolb, 1975; Kolb & Famiglietti, 1976; Vaney et al., 1991b; Strettoi et al., 1992). Quantitative analysis of serial sections of one particular rabbit AII cell (Strettoi et al., 1992) identified 21 lobular appendages ranging in diameter from 1.6 – 5.5um. In contrast, the processes that form the dendritic tree in sublamina b are called the distal (or arboreal) dendrites and terminate predominantly in stratum 5. The distal dendrites are thin processes that possess spines along their length and branch more widely than the lobular appendages (Figure 1a). The above characteristics are conserved in rabbit, rat, cat, and macaque monkey retinas (Kolb et al., 1976; Vaney, 1985; Kolb et al., 1992; Wassle et al., 1993; Wassle et al., 1995; Mills & Massey, 1999).

AII distribution and morphology is different in central versus peripheral retina. AII density is greatest in extrafoveal central retina and decreases with increasing eccentricity. Simultaneously, both dendritic fields enlarge with eccentricity (Fig. 2a) (Kolb et al., 1981; Mills & Massey, 1991; Vaney et al., 1991a; Vaney et al., 1991b; Wassle et al., 1993), with a more pronounced change reported for the distal dendrites. For example, AII cell density in central cat retina is maximal at 5300 cells/mm2 and decreases to 500-800 cells/mm2 in peripheral retina. The diameter of the lobular appendage field increases from 16um (central retina) to 30um (8mm eccentricity); whereas, the diameter of the distal arbor expands from 18um to 58um (Vaney, 1985) (Fig.2b). This morphological trend has also been identified in other mammalian retinas.

 


Fig. 2a. Golgi stained AII cells in wholemount views of human and cat retina.

Fig. 2b. AII amacrine cells stained with Lucifer Yellow and viewed in whole-mounts reveal two distinct types of processes. In sublamina a, the shorter lobular dendrites (A) encircle the cell body, while in sublamina b, thin distal dendrites (B), end in stratum 5 (From Mills & Massey, 1991).

The distal dendrites in sublamina b of adjacent AII cells overlap. The amount of overlap has been quantified by calculating the coverage (dendritic field area x cell density) of each cell (Casini et al., 1995). In rabbit, a coverage value of 1.8 was calculated for distal dendrites in the central retina (visual streak) and 2.4 in the inferior retina. The greatest overlap is seen in the superior peripheral retina, where a coverage value of ~10 was calculated (Vaney et al., 1991a). In contrast, there is little or no overlap between the lobular dendrites in sublamina a of adjacent rabbit AII cells, as coverage varied from ~1.0 in the inferior retina and ~0.8 in the superior retina (Vaney et al., 1991a) were calculated. These values show that the lobular appendages maintain a constant coverage over the entirety of the retinal area; while the distal processes vary in overlap along both central-to-peripheral and superior-to-inferior axes. Similar differences in AII dendritic processes have been reported in cat, monkey, and rat, suggesting differences in function between AII processes in the distal and proximal IPL (Vaney, 1985; Wassle et al., 1993; Wassle et al., 1995).

 

3. Synaptic connectivity.


Fig. 3. Electron micrographs from serial sections showing the ultrastructure of types of synapses AII cells make in the IPL.

 

Chemical inputs to distal dendrites in sublamina b

The AII receives direct glutamatergic inputs in sublamina b (s5) from rod bipolar cells (RBC)(Fig.3). At this synapse, the AII forms one member of the postsynaptic dyad (Kolb & Famiglietti, 1974; Famiglietti & Kolb, 1975; Strettoi et al., 1990; Strettoi et al., 1992; Chun et al., 1993; Kim et al., 1998); the other member (discussed below) is a GABA-containing amacrine cell known as A17 in cat and S1/S2 in rabbit (Massey et al., 1992). The latter cell types make reciprocal synapses back onto the RBC terminal at GABAc receptors on the RBC (Sandell et al., 1989; Grunert & Wassle, 1990; Strettoi et al., 1990; Chun et al., 1993; Kim etal., 1998; Zhang et al., 2002). Each AII receives input from several RBCs.

In all mammals, physiological studies show glutamate-elicited currents in AII amacrine cells are mediated by AMPA-preferring receptors (Boos et al., 1993; Cohen & Miller, 1999; Morkve et al., 2002) sensitive to the non-selective antagonist CNQX and the AMPA receptor specific compounds GYKI-52466 and cyclothiazide (Morkve et al., 2002; Singer & Diamond, 2003; Veruki et al., 2003). The receptors are formed from GluR3 (Dacheux & Raviola, 1986; Qin & Pourcho, 1999a, 1999b; Gabriel et al., 2002) and/or GluR4 (Ghosh et al., 2001; Li et al., 2002) subunits (Fig. 4), which confer high calcium permeability to the channel.

Fig. 4. Immunostaining of AII distal dendrites (calretinin, green) and rod bipolar cell terminal (protein kinase C, blue). The yellow/white dots idicate immunostaining for GluR4 receptors at the rod bipolar-AII amacrine synapses. From Li et al.2002.

NMDA responses have also been identified on rat (Hartveit & Veruki, 1997) and rabbit (Bloomfield & Xin, 2000) AII cells. These findings contradict immunocytochemical studies which note the absence of NMDA receptor subunits on AII dendritic processes (Hartveit et al., 1994; Goebel et al., 1998; Fletcher et al., 2000; Grunert et al., 2002). Recent findings indicate NMDA responses do not mediate transmission at the RBC-to-AII synapse (Singer & Diamond, 2003), suggesting these receptors, when present, may be located extra-synaptically. The NMDA response in AII cells may also depend on an intracellular signaling pathway, as the response runs down quickly in patch clamp studies (Hartveit & Veruki, 1997).

Though one AII amacrine cell is associated with almost all RBC dyads rod bipolar connections comprise only ~30% of the inputs to AII cells (Strettoi et al., 1992). These cells also receive chemical inputs from other amacrine cells within s1 and s5 in rabbit; s1, s3-s5 in rat and cat and in monkey. The amacrine cell(s) presynaptic to AII distal dendrites have not generally been identified, except for dopaminergic amacrine cells in cat (Kolb et al., 1990). Amacrine contacts comprise ~40% of the synaptic inputs in sublamina b according to Strettoi et al., (1992).

 

Electrical connections of distal dendrites in sublamina b

AIIs are electrically coupled to ON cone bipolar cells (CBC) throughout sublamina b (Fig. 3) (Kolb and Famiglietti, 1974: Famiglietti and Kolb, 1975: Kolb, 1979; Strettoi et al., 1992; Veruki & Hartveit, 2002a) and to other AII cells in s5 (Strettoi et al., 1990; Strettoi et al., 1992; Strettoi et al., 1994). AII/AII junctions are structurally formed from connexin 36 (Feigenspan et al., 2001; Mills et al., 2001). Signal propagation is bidirectional, promoting synchronized responses (i.e., action potentials) among connected cells (Veruki & Hartveit, 2002b).

Dopamine application reduces AII/AII coupling (Mills & Massey, 1995) through the activation of D1-type dopamine receptors (Hampson et al., 1992) and the formation of cAMP (Fig. 5a)(Hampson et al., 1992; Cooper et al., 1996). In contrast, gap junctions formed between AII and ON-CBC are heterologous, formed by connexin 36 on AII processes and either connexin 36 or another (possibly 45) connexin on CBC (Feigenspan et al., 2001; Mills et al., 2001; Lin et al., 2005). These junctions are also bidirectional (Cohen & Miller, 1999; Bloomfield & Xin, 2000; Trexler et al., 2001), though signals are more effectively propagated in the direction, AII to ON-CBC (Veruki & Hartveit, 2002a). The permeability of AII/ON-CBC channels appears to be regulated by nitric oxide and cGMP (Mills & Massey, 1995). Nitric oxide activates guanylate cyclase, increasing intracellular cGMP, and decreases coupling between these cell types.

 


Fig. 5a. Dopamine application to retina when the AII cells are injected with biocytin, cause a reduction in the numbers of cells that are coupled via gap junctions as compared normal conditions. Cat retina. From Vaney (1994)

Fig. 5b Coupling between AII cells changes with level of illumination. In dark-adapted (starlight/scotopic) rabbit retinas (A), only a small number of AII amacrine cells are coupled. Retinas that are light-adapted at low/mesopic/twilight intensities (B) display the greatest degree of AII coupling. When light-adapted at the cone threshold/daylight (C), the extent of AII/AII coupling decreases to a value similar to (A). These observed changes in AII/AII coupling reflect changes in the diameter of the receptive field center. Overall coupling between AII/ON-cone bipolar cells did not vary with light level. Bloomfield and Dacheux, 2001.

The reported extent of coupling among AII cells varies greatly, from modeling estimates that each AII is coupled to three other AII cells (Vardi & Smith, 1996) to dye-coupling studies showing the network can range from ~20 to >300 coupled cells (Vaney, 1991; Bloomfield et al., 1997). This difference in coupling extent is dependent upon adaptational state (Fig. 5b). Changes in AII/AII coupling have been shown to reflect changes in the diameter of the receptive field center (Figure 5b). For example, in dark-adapted tissue, one AII cell is coupled to a network of ~20 other cells, and the corresponding diameter of the receptive field center averages ~74 um (Bloomfield et al., 1997). When the intensity of light is increased, but still within the operating range of the cell (~2.25 log intensity unit), both the extent of coupling and the diameter of the receptive field center increase (Fig. 5b). Further increases in light intensity actually results in a decrease in coupling to levels comparable to those seen in dark-adapted conditions (Fig.5b). Thus, the cells are extensively coupled over their operating range, but uncouple at the edges of this range.

What is the benefit of varying the extent of coupling? AII/AII coupling is integral in optimizing the signal-to-noise ratio of the AII network (Bloomfield et al., 1997; Bloomfield & Dacheux, 2001) as it allows the smaller correlated rod signals to be increased while uncorrelated noise is decreased (Smith & Vardi, 1995; Vardi & Smith, 1996). This would be important when the retina is operating at dim light intensities (mesopic conditions) as increased coupling maximizes the area from which each AII can merge spatially correlated signals, thereby increasing signal to noise ratio. In dark-adapted conditions, however, a miniscule number of photons are intermittently absorbed by the rods and the correlated signals are few (Bloomfield & Dacheux, 2001). As coupled AII cells all receive common inputs, AII coupling would strengthen the response by summing correlated signals and reducing noise (Smith & Vardi, 1995; Vardi & Smith, 1996). However, given that the number of correlated signals reaching the AII network is few, extensive coupling at these low light levels is of no advantage as it would increase background noise, causing the faint signals to spread laterally and decrease the overall amplitude of the response. Coupling is also reduced in light-adapted conditions, reducing the transmission, and loss, of cone signals through the AII network facilitating the high spatial acuity in photopic conditions (Bloomfield & Dacheux, 2001). Further, the high signal-to-noise levels in the cone system reduce the need for spatial averaging.

Fig. 6. The AII has synaptic contacts throughout the inner plexiform layer (IPL), including synapses with both rod (RB) and cone bipolar (CB) cell types. AII cell processes are postsynaptic to rod bipolar terminals in sublamina b (red circle). In this region, the terminal dendrites also participate in gap junctions (*, blue rectangle) with other AII cells and with ON-CB. In sublamina a, AII cells form synapses (often reciprocal) with OFF-CBC processes (blue circle). GC, ganglion cell; ON, ON-center; OFF, OFF-center. Open arrowheads indicate sign-inverting synapses; filled arrowheads indicate sign-conserving synapses. From Xin and Bloomfield, 1999.

Gap junctions between AII/ON-CBC provide the mechanism through which rod signals reach ON-ganglion cells (Kolb, 1979) via the circuit: rod to rod bipolar to AII to ON-cone bipolar cell to ON-ganglion cell (Fig.6, red circle, blue square). As these gap junctions are also bidirectional, they provide an alternate pathway through which AIIs receive cone-driven inputs (DeVries & Baylor, 1995; Cohen & Miller, 1999; Xin & Bloomfield, 1999). The alternative route would be through rod/cone gap junctions thus getting rod signals into cone photoreceptors themselves (Nelson, 1977). Rod signals would be transmitted to cone bipolar cells and then pass to AIIs in the circuit rod -cone – ON-cone bipolar -AII (DeVries & Baylor, 1995). Signals originating in cone photoreceptors would be relayed via this path as well and cone-driven responses have been recorded in AII cells (Nelson,1982; Xin & Bloomfield, 1999). Photopic inputs from ON-CBC depolarize AII cells which, in turn, hyperpolarize OFF-CBC (Fig. 6) suppressing light-adapted OFF-center responses (Xin & Bloomfield, 1999). As noted above, AII/ON-CBC junctions appear to be modulated by NO, but not by light as physiological studies report changes in background light levels do not alter the observed overall extent of AII/ON-CBC coupling (Bloomfieldm et al. 1997) and cone-driven responses can be recorded from AII cells in photopic conditions (Nelson, 1882; Xin & Bloomfield, 1999).

Given the morphological diversity of CBC types, it is useful to identify which specific cell(s) is/are coupled to AIIs to better understand the underlying circuitry. Mills and Massey (1996) identified electrical coupling between AIIs and the calbindin-positive bipolar cell in rabbit. However, as only one-quarter of the bipolar cells (23%) tracer-coupled to AIIs are calbindin-positive, more than one type of ON-CBC probably makes gap junctions with AIIs (Massey & Mills, 1996; Kim et al., 2004). In agreement with this, a recent study by Veruki & Harveit (2002a) examining the electrical properties of AII/ON-CBC gap junctions in rat identified four types of bipolar cells, namely CB5-CB8 electrically coupled to AIIs in rat (Euler et al., 1996). Furthermore the latest evidence from Masland’s group suggest that some of the ON cone bipolars coupled to AII cells express connexin 45 but not connexin 36 (Lin et al., 2005. In cat, the cb5 bipolar cell was found to be coupled to AII processes (Nelson & Kolb, 1983). The cb5 bipolar cell probably corresponds to the calbindin bipolar cell in rabbit, as the latter makes the greatest number of gap junctions with AII cells (Strettoi et al., 1994).

Thus, electrical coupling within the AII network functions to maximize signal transmission to postsynaptic ganglion cells. As AIIs receive both rod- and cone-driven inputs, the caliber of the signal varies depending on stimulus intensity. Consequently, the dynamics of the AII network must also vary continuously. In contrast, synaptic transmission through AII/ON-CBC gap junctions is not affected by adaptational state (Bloomfield et al., 1997), suggesting this pathway may function on a sustained level continually relaying signals independent of light level to ganglion cells.

 

Synapses of the lobular appendages in sublamina a

The lobular appendages are the major chemical synaptic output sites of AII amacrine cells (Fig. 3)(Famiglietti and Kolb, 1975; Strettoi et al., 1992). These appendages form reciprocal, inhibitory synapses in s1-s2 (Strettoi et al., 1992) with OFF-CBC terminals (Kolb & Nelson, 1983; Strettoi et al., 1992; Chun et al., 1993; Merighi et al., 1996). These synapses account for 90% of the output from AII cells in rabbit (Strettoi et al., 1992). AII amacrine cells in rabbit rarely synapse directly onto OFF-ganglion cells whereas in cat and monkey synapses to OFF ganglion cells are common (Kolb, 1979). Inhibitory signals from AIIs are passed to OFF-CBC, decreasing glutamate release onto OFF-type ganglion cells during light stimulation (Fig. 6, blue circle).

Merighi et al (1996) have shown in rabbit that at least two different OFF-CBC types (DAPI-Ba1 and DAPI-Ba2) are postsynaptic to AII cell lobular appendages in different regions of the IPL. The axon terminal of DAPI-Ba1 cells ramifies in s2, while DAPI-Ba2 cells are multistratified with boutons located within s1-s3. In cat, cb1 and cb2 bipolar cells (Kolb et al., 1981), which correspond to DAPI-Ba2 and DAPI-Ba1 cells, respectively, contact AII cells in sublamina a. In primates, AII lobular appendages participate in reciprocal synapses with calbindin positive DB3 axon terminals in s2 (Jacoby & Marshak, 2000). Another bipolar cell in macaque, DB2, is similar in stratification pattern to the rabbit DAPI-Ba2.

Fig. 7. A dopaminergic amacrine cell immunolabeled for Tyrosine hydroxylase TOH+ (TOH+green) has fine terminal dendrites “rings” that surround AII amacrine cell bodies (red, AII)in S1 of the IPL. Courtesy Nicolas Cuenca.

Both AII dendrites and the cell body are postsynaptic to other amacrine cells in S1. Double labeling studies have shown that the dendrites of dopaminergic amacrine cells encircle AII somata, forming characteristic rings as shown in Figure 7 (Pourcho, 1982; Voigt & Wassle, 1987; Kolb et al., 1991). These dopaminergic inputs are believed to mediate changes in AII/AII coupling that occur with adaptational state. However, recent findings show that direct contacts between the dopaminergic processes and AII somata are GABAergic rather than dopaminergic (since dopaminergic amacrines are said to be also GABA positive, Contini & Raviola, 2003). Thus, AII cells may receive direct GABAergic inputs at the cell body which could also regulate AII cell light responses. These GABA-elicited responses, from GABAA receptor activation, would result in a faster modification of AII responses compared to dopamine actions which are mediated through slower second messenger cascades and may be considered paracrine in nature. It has to be mentioned here that the dopaminergic amacrine cell is now considered to contain glutamate (Jones and Marc, 2004) and if this is the case, a faster transmitter action would also be expected.

 

4. Physiological responses

AII cells themselves are inhibitory glycinergic neurons (Pourcho, 1996; Menger et al., 1998). Their strongest response, and unique role, is during scotopic levels of illumination. In this case, the AII assists in increasing both the speed of transmission and the amplitude of the rod signals seen by the ganglion cells (Nelson, 1982).

AII amacrine cells are also called the “rod amacrine cell” because they have response characteristics, such as threshold, saturation level, and spectral sensitivities, similar to rods (Nelson, 1982; Bloomfield & Dacheux, 2001). These cells display complex physiological responses that serve both rod and cone retinal pathways and are sensitive to adaptational state (Fig. 8a). In general, AIIs generate TTX-sensitive action potentials and respond to the exogenous application of GABA, glycine, and glutamate (Boos et al., 1993). AIIs are classified as ON-center amacrine cells that display center-surround antagonism (Nelson, 1982; Dacheux & Raviola, 1986; Xin & Bloomfield, 1999) when dark-adapted; surround antagonism is abolished in light-adapted cells (Xin & Bloomfield, 1999).

Generation of the ON-center response

Based on the synaptic connections of AII cells, ON-center responses could be generated via two pathways: (1) direct rod-driven inputs from (ON-type) RBC at chemical synapses or (2) direct cone-driven inputs from (ON-type) CBC via electrical synapses. Physiological recordings showing rod- and cone-driven responses in AII cells and pharmacological studies indicate ON-center responses are blocked by the application of APB (2-amino-4-phosphonobutyric acid), indicating they are generated by ON-type bipolar cells (Xin & Bloomfield, 1999).

 


Fig. 8a. In dark-adapted conditions (A, left) an ON-center response was recorded at all light intensities tested (threshold = log -6.75). The amplitude of the ON-center response increased with increasing light intensity until saturation at ~ log -4.5 to log -4.0. An ON-center response was also recorded from light-adapted cells (A, right), though the threshold under these conditions was higher (~ log -4.0). The light-adapted ON-center response also increased with increasing light intensity, but reached saturation (log -1.0 to 0.0) at a higher light intensity than dark-adapted AII’s. From Xin,and Bloomfield, 1999.

Fig. 8b Schematic diagram showing the circuitry underlying AII ON-center responses. In dark-adapted conditions, the scotopic ON-center response results from direct glutamatergic inputs from rod bipolar cells (RB) (blue arrow). In contrast, cone-driven ON-center responses occur as AIIs are depolarized by signals relayed through AII/ON-CB gap junctions (red arrow). Both of these inputs occur onto the distal dendrites in sublamina b. Light-adapted AIIs also display a small, transient OFF-center responses due to direct inputs from OFF-CB onto lobular appendages in sublamina a (dashed arrow). The ON- and OFF-center responses of light-adapted AII cells are generated simultaneously. From Xin,and Bloomfield, 1999.

How is the ON-center response generated? Interestingly, signals transmitted within both of the above pathways can generate the center response, with the contributions of each pathway varying depending on the intensity of the stimulus (Figure 8b). In dark-adapted conditions, center responses are derived from rod-driven or cone-driven inputs transmitted directly to AIIs from rod BCs or from cone BCs through gap junctions. Exogenous application of either 8-bromo-cGMP or SNAP, which uncouple AII/ON-CBC gap junctions, does not block scotopic ON-center responses but does block the cone signal component. Bright stimuli saturate the rods reducing rod-driven inputs to AIIs. In these conditions, ON-center responses are blocked when AII/ON-CBC junctions are pharmacologically uncoupled (Xin & Bloomfield, 1999). Thus, the ON-center responses in AII cells comes from either rods or cones. Rod signals depolarize AIIs in dark-adapted (scotopic) conditions; cone-driven signals are relayed in light (photopic) conditions (Figure 8a and b). Interestingly, a temporary OFF-center response has also been identified in light-adapted AII cells. This response is blocked by CNQX and is believed to be generated via direct glutamatergic inputs from OFF-cone bipolar cells onto AII lobular appendages in sublamina a (Xin & Bloomfield, 1999).

Fig. 9. The waveform of the AII amacrine cell reaches its maximum amplitude more rapidly than the presynaptic rod bipolar cell. At the peak of the AII cell’s response, the response of the rod bipolar is only one-third of its maximum amplitude. Trace at bottom indicates the duration of the light stimulus. From Nelson, 1982.

The AII light response is biphasic, with an initial transient depolarization followed by a more sustained component (Figure 9). This allows the AII to respond faster to a light stimulus than the presynaptic rod bipolar cell and to reach its maximum amplitude more rapidly. In fact, at the peak of the AII response, the rod bipolar response is one third of its maximum amplitude (see Figure 9). The AII cell also repolarizes at a faster rate (Nelson, 1982). The transient nature of the AII light response is unexpected as both presynaptic RBC (Dacheux & Raviola, 1986) and rod photoreceptors generate slow sustained responses. This leads to the conclusion that the change from a sustained to a transient signal originates in the AII and serves to quicken rod signals relayed to the inner retina (Nelson, 1982). What underlying mechanism accounts for the change in response kinetics? This question was answered in a recent paper by Singer & Diamond (2003). They examined the RBC/AII synapse using dual patch clamp techniques in rat retinal slices. The transient component of the AII response was not due to feedback inhibition onto RBC or to postsynaptic AMPA receptor desensitization, because it was present when either picrotoxin or cyclothiazide was applied. However, the EPSC waveform did vary with calcium influx into the presynaptic terminal suggesting that activation of calcium channels limits the rate of exocytosis. The authors conclude that the initial transient component of the AII light response is due to the rapid rate of neurotransmitter release from RBC terminals coupled to the fast kinetics of postsynaptic AMPA receptors (Singer & Diamond, 2003).

 

Generation of the OFF-surround response

In the initial physiological characterization of AIIs, surround responses were only identified in some cells (Nelson, 1982). Subsequently, it was shown that the antagonistic surround is present only when cells are dark-adapted (Xin & Bloomfield, 1999; Bloomfield & Xin, 2000). A reasonable hypothesis, given AII morphology, would be that the surround is generated through connections between AII cells and OFF-CBC, as this synapse would be functioning in dark-adapted conditions. Hoever, the surround response is blocked by CNQX (consistent with a role for OFF-CBC), and is also blocked by APB, suggesting the surround originates at rod bipolar synapse(s) in the IPL (sublamina b), although RBC themselves do not display center/surround organization (Xin & Bloomfield, 1999; Bloomfield & Xin, 2000).

Two pathways have been proposed to account for the circuitry underlying the OFF-surround response (Fig. 10)). First, another amacrine cell may synapse directly with and provide inhibitory inputs to AII distal dendrites, as suggested by anatomical studies. Second, inhibitory feedback synapses onto RBC terminals from A17 amacrine cells may generate surround responses (i.e., (Bloomfield & Xin, 2000; Volgyi et al., 2002). Recent evidence favors this latter pathway, which is summarized below (Figure 10).

Fig. 10. The AII surround response could be generated by two possible pathways. The first pathway involves direct inputs from a GABAergic amacrine cell (labeled with a ‘?’) presynaptic to the distal dendrites in sublamina b. These synapses have been described in many species, though the specific presynaptic cell has not been identified. The second pathway involves an indolamine-accumulating amacrine cell (S1, A17 in cat) which releases GABA at reciprocal synapses onto rod bipolar (RB) terminals. In this diagram, presentation of a light stimulus in the surround region of the AII cell’s receptive field (gray circle, left) depolarizes the rod bipolar cell, leading to a release of glutamate onto the process of an S1 amacrine cell (gray circle to the left). The depolarizing signal is transmitted centrally where the S1 process (yellow circle) releases GABA onto the rod bipolar terminal. GABA inhibition of the rod bipolar cell reduces subsequent release of glutamate onto the AII cell. Experiments suggest that it is the pathway involving the S1 cell is what generates the AII surround response. From Bloomfield and Xin, 2000.

The A17 amacrine cell in cat, rat, and monkey is equivalent to the S1/S2 indolamine-accumulating amacrine cell in rabbit (Sandell et al., 1989). This cell, like the AII, is rod-driven (Nelson & Kolb, 1985) and transmission from RBC to A17 cells in rat is blocked by CNQX (Hartveit, 1999). In other species, however, immunocytochemical studies have identified metabotropic glutamate receptors (Cai & Pourcho, 1999) and GluR1/2 receptor subunits (Ghosh et al., 2001; Li et al., 2002) on A17 dendrites. These findings suggest that information flow across the RBC dyad may be mediated by several different glutamatergic mechanisms (Ghosh et al., 2001; Li et al., 2002). Cat A17 cells display a sustained light response and lack an antagonistic surround (Nelson & Kolb, 1985); whereas, center-surround antagonism has been reported for rat A17 cells (Menger & Wassle, 2000).

A17 and S1/S2 amacrine cells make reciprocal contacts onto RBC terminals. A17 cells contain GABA (Porcho and Goebel, 1983; Grunert & Wassle, 1990; Massey et al., 1992; Kim et al., 1998) and inhibit RBC through the activation of GABAc receptors (Zhang et al., 2002; Dong & Hare, 2003). This GABAergic feedback is modulated by light intensity, the activation of GABAA receptors (Dong & Hare, 2003) also present on rod bipolar terminals (Euler & Wassle, 1998; Fletcher & Wassle, 1999; McGillem et al., 2000; Volgyi et al., 2002), and the activation of presynaptic mGluR1/5 receptors (Euler & Wassle, 1998). Physiologically, this feedback changes rod bipolar responses, making the scotopic b-wave more transient (Dong & Hare, 2003), and may be involved in altering calcium currents in RBC terminals (Pan, 2001), ultimately modifying glutamate release contributing to the surround mechanism in both ganglion cells (Shields & Lukasiewicz, 2003) and AII amacrine cells (Volgyi et al., 2002).

In cat, the A17 cell is always the other member of the postsynaptic dyad with AII amacrine distal processes, although other amacrine cell types also receive inputs from rod bipolar cells (Kolb & Nelson, 1983). In contrast, in rabbit, either the S1 or the S2 indolamine-accumulating amacrine cell could partner with the AII at the dyad. Why is this synapse more complex in rabbit? The answer can be found in the differences in morphology and coupling extent between these two cell types. S1 cells are wide-field amacrine cells that display extensive coupling with other S1 cells (i.e., up to ~130 cells coupled), while S2 cells are smaller and not as extensively coupled (maximum of 35 cells coupled) (Li et al., 2002). These differences suggest that S1 cells provide a wide-field component to the AII surround response, while S2 cells provide inputs from a more local circuit (Li et al., 2002; Zhang et al., 2002).

 

5. Role in duplex vision.

The AII amacrine is the place where rod and cone pathways, as well as ON- and OFF-pathways cross. It is central to scotopic (night) vision. The complex physiology of AII cells is paralleled by their diffuse morphology: their processes are located throughout the IPL and synapses have been observed within all strata (i.e., chemical synapses in s1, s2, and s5; electrical synapses in s3, s4, and s5). Due to these connections, and the parallel retinal pathways, AII amacrine cells always receive inputs, providing the inner retina with a sustained inhibitory pathway (Cohen & Miller, 1999).

Within the rod pathway (or scotopic levels of light), light stimulated decrease in rod photoreceptor glutamate release depolarizes rod bipolar cells, in turn causing the release of glutamate from rod bipolar terminals onto the postsynaptic dyad elements: the indolamine-accumulating or the A17 amacrine cell and the AII amacrine cell. Glutamate excites the AII, resulting in three simultaneous synaptic events: (1) the release of glycine onto OFF-CBC, ultimately inhibiting OFF-ganglion cells, (2) the depolarization of ON-CBC (via AII/ON-CBC gap junctions) and the subsequent depolarization of ON-ganglion cells, and (3) and increase in signal to noise ratio due to the spread of the signal among the coupled AII network. In addition, cat, monkey and rat AII cells synapse directly onto OFF-ganglion cells, resulting in direct glycinergic inhibition of these cells (i.e Muller et al. 1988). AII responses are modified by inhibitory inputs from depolarized A17 (S1/S2) cells which feedback onto rod bipolar terminals. The overall effect is inhibition of the OFF-pathway and excitation in the ON-pathway both by rod-driven signals.

In bright light (photopic) conditions, ON- and OFF-center responses have been recorded from AII cells (Xin and Bloomfield, 1999). Both responses are generated via inputs from CBC, with the transient OFF-center response arising from glutamatergic inputs from OFF-CBC and the ON-response arising transmission through ON-CBC/AII gap junctions. While both ON- and OFF-responses may be found in the same AII cell, the ON-center response predominates. These inputs from ON-CBC depolarize the AII cells, causing glycinergic inhibition of OFF-CBC and OFF-ganglion cells (Muller et al., 1988). In addition, under bright light conditions, coupling within the AII network is reduced, preventing the dissipation of cone signals prior to reaching the ganglion cells. The overall result, again, is that the OFF-pathway is inhibited by the ON-pathway while high acuity cone signals are maintained. In this way the AII mixes not only rod and cone signals, but ON- and OFF-pathways.

Thus, the inclusion of the AII in the rod circuit (scotopic conditions) is required for the vertical flow of information within the IPL, as it functions to amplify the signal, increase transience, and reduce noise prior to reaching the ganglion cells. In cone-driven circuits, inputs from ON-CBCs directly stimulate AIIs and ON-ganglion cells. The AII response is a depolarization, with robust ON-center response, resulting in glycine release and the inhibition of OFF-type responses. These glycinergic inputs to postsynaptic CBC and/or ganglion cells allow ON-signals to predominate in the inner retina under these conditions. Thus, AII is always receiving inputs, though the type of input varies (depending on stimulus intensity) causing the AII cell to “shift its focus” from one input pathway to another and from one function to another.

 

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Mahnoosh Farsaii and Victoria P. Connaughton

Last Updated: July, 2011.