the vertebrate retina is a beautifully laminar structure comprising five major neuronal cell types ( figure 1 ) . photons are absorbed by rod and cone photoreceptors , which transduce light energy into a neural signal that is transmitted to bipolar cells . nine types of bipolar cell in the mammalian retina receive their input from cones ( wassle et al . , 2009 ) ; a tenth type , the rod bipolar cell ( rbc ) , receives its input from rods . cone bipolar cells make excitatory synapses directly onto ganglion cells ( gcs ) , whereas rbcs contact aii ( a2 ) amacrine cells , which relay the on signal from the rbc to on and off cone bipolar cell terminals via sign - conserving ( electrical ) and sign - inverting ( glycinergic ) synapses , respectively . this excitatory pathway is modulated by two laterally oriented , inhibitory networks . in the outer retina , horizontal cells provide feedback to generate the first center - surround receptive fields in the visual pathway ; several dozen amacrine cell types in the inner retina provide feedback and feedforward inhibition that sharpens the temporal properties of visual signaling and contributes to more complex visual processing . in the mammalian retina , only gcs , whose axons are bundled together in the optic nerve , and some amacrine cells fire action potentials . presynaptic active zones in photoreceptors ( figure 1b ) and bipolar cells ( figure 1c ) have evolved  ribbon  structures that are thought to regulate the delivery of synaptic vesicles to release sites and thereby sustain ongoing transmitter release ( parsons and sterling , 2003 ) . cp - gluar expression in the retina . ( a ) schematic of mammalian retina ( vaney et al . , 1991 ) . cp - gluar  +  cell types are highlighted in amber ; gcs are hatched because the express cp - gluars primarily early in development . r , rod ; c , cone ; rb , rod bipolar cell ; hc , horizontal cell ; cb , cone bipolar cell ; g , ganglion cell ; onl , outer nuclear layer ; opl , outer plexiform layer ; inl , inner nuclear layer ; ipl , inner plexiform layer ; gcl , ganglion cell layer . ( b ) schematic showing triad synapse in the opl between presynaptic cone photoreceptors and postsynaptic horizontal cells and bipolar cells . modified from devries ( 2000 ) . ( c ) schematic showing dyad synapse in ipl between presynaptic rod bipolar cell and postsynaptic a17 and aii amacrine cells . in ( b , ( d ) co staining in the p11 rat retina shows functional cp - gluar expression in horizontal cells , amacrine cells , and ganglion cells ( osswald et al . , 2007 ) . ( e ) cp - gluar expression is reduced in adult ganglion cells ( osswald et al . , 2007 ) . cells expressing functional cp - gluars can be identified by a procedure that stains cobalt ( co ) , a divalent cation that permeates the cp - gluar pore ( pruss et al . , 1991 ) . first , the tissue is stimulated with a gluar agonist added to extracellular solution containing cocl2 , then rinsed in solution containing ( nh4)2s , which reacts with the intracellular co to form cos precipitate . silver enhancement stains the precipitate a deep amber , clearly identifying co - loaded cells ( figure 1d ) . when cocl2 is applied to retinal slices in the presence of nmda receptor antagonists , the consequent cos precipitation is blocked completely by gluar antagonists and , except in special cases ( discussed below ) , polyamine antagonists of cp - gluars , indicating specific labeling of cp - gluar - expressing cells ( osswald et al . , 2007 ) . in the embryonic chick retina , the cp - gluar - specific co staining technique robustly labels horizontal cells , amacrine cells , and gcs ( allcorn et al . , 1996 ) , consistent with reported cp - gluar - mediated currents in cells dissociated from embryonic chick retina ( catsicas et al . , 2001 ) and ca imaging experiments showing agonist - activated ca in the outer plexiform layer ( opl ) , inner plexiform layer ( ipl ) , and gc layer ( gcl ; sugioka et al . , 1998 ) . similar co staining patterns are observed in the juvenile rat retina ( figure 1b ; leinders - zufall et al . , 1994 ; gc staining in rat decreases substantially following eye opening ( p14 ; figure 1e ; osswald et al . , 2007 ) , but gcs isolated from neonatal rat retina exhibit cp - gluar - mediated currents ( rorig and grantyn , 1993 ; leinders - zufall et al . , 1994 ; zhang et al . , 1995 ; otori et al . , 1998 ) and ca signals ( leinders - zufall et al . , 1994 ; although cp - gluar - mediated currents have been reported in cat bipolar cells ( sasaki and kaneko , 1996 ) , the large majority of work has been focused on horizontal cells , amacrine cells , and gcs . the remainder of this review will highlight the distinct , interesting roles that cp - gluars play in each of these cell types . functional cp - gluars have been found in horizontal cells of every species investigated , including lizard ( jackman et al . , 2011 ) , fish ( eliasof and jahr , 1997 ; huang and liang , 2005 ; sun et al . , 2010 ) , skate ( kreitzer et al . , 2009 ) , and rabbit ( rivera et al . , 2001 ; figure 1b ) . catfish cone horizontal cells , stellate neurons with enormous somata ( sakai and naka , 1986 ) , express extraordinarily fast cp - gluars : in excised membrane patches at room temperature , glutamate - evoked currents desensitized with a time constant of 1  ms and recovered from desensitization with a time constant of less than 9  ms ( eliasof and jahr , 1997 ) . these rapid kinetics , rivaled only by gluars receptors in avian auditory nuclei ( raman and trussell , 1992 ) , suggest that cp - gluars may mediate local signaling in horizontal cell processes , because such brief conductances would be filtered strongly by the large membrane capacitance of the cell . local signaling in horizontal cells has long been known to mediate negative feedback onto photoreceptors , but the identity of the underlying mechanism remains controversial ( kamermans et al . , 2001 ; hirasawa and kaneko , 2003 ; hirano et al . , 2005 ; vessey et al . , a recent report has introduced an intriguing wrinkle by providing evidence for positive feedback signaling onto cone photoreceptors that involves cp - gluars on horizontal cells ( jackman et al . , 2011 ) . vesicle release was measured from cone photoreceptors in lizard retinal slices ( anole lizards express only cone photoreceptors ) using the membrane dye fm1 - 43 . applied through the superfusion solution , fm1 - 43 integrates into membranes and is taken up into presynaptic terminals via membrane endocytosis . when fm1 - 43 is washed from the extracellular solution , fluorescent vesicles remain in the presynaptic terminal until released . cones release synaptic vesicles constantly in the dark , and so the fm1 - 43 signal in cone terminals decayed steadily following loading . the authors found , surprisingly , that exogenous glutamate application accelerated fm1 - 43 destaining ( i.e. , vesicle release ) in cone terminals ( jackman et al . , 2011 ) . this effect was mimicked by ampa and blocked by cp - gluar receptor antagonists , despite the fact that cones express no functional gluars . accelerated release was observed only in thick slices , suggesting a role for laterally oriented neurons like horizontal cells . these results suggested that activation of cp - gluars on horizontal triggers some feedback signal to enhance release from cones . depolarizing horizontal cells only diminished release from cones , however , likely reflecting the previously described negative feedback . instead , release from cones was accelerated by uncaging ca in neighboring horizontal cells , suggesting that ca entering through cp - gluars actually triggers release of a retrograde signal from horizontal cells . similar effects of gluar agonists on photoreceptor release were observed in salamander , zebrafish , and rabbit . the identity of the retrograde signaling molecule and the physiological role of the positive feedback remain to be determined . cp - gluars in horizontal cells appear to undergo a developmental change in their sensitivity to external polyamines ( osswald et al . , 2007 ) . prior to eye opening ( p14 ) , co staining in horizontal cells is completely blocked by extracellularly applied polyamine toxins . in the few days following eye opening , however , horizontal cells become insensitive to polyamines and remain insensitive into adulthood ( figure 2a ) . interestingly , this pharmacological shift is prevented by rearing mice in the dark , indicating that light - evoked activity triggers the change ( osswald et al . , 2007 ) . although the mechanism underlying this phenomenon has not been identified , it may reflect a developmental increase in transmembrane gluar regulatory protein ( tarp ) expression , which has been shown to diminish gluar sensitivity to intracellular polyamines ( soto et al . , 2007 ) . ( a ) cp - gluars in horizontal cells become insensitive to polyamines around the time of eye opening ( p14 ) . ( b ) in aii amacrine cells , cp - gluars occupying the on portion of the ipl recover polyamine sensitivity about 2  weeks after eye opening , whereas cp - gluars in the off layer remain insensitive into adulthood ( dark gray bar ; osswald et al . , 2007 ) . the amacrine cell class comprises perhaps 30 different subtypes ( macneil and masland , 1998 ) , only a small subset of which have been studied in any detail . in that select group , however , cp - gluars appear to figure prominently . both aii and a17 amacrine cells mediate synaptic input from rbcs through cp - gluars ( morkve et al . , 2002 ; , 2006 ; figure 1c ) . besides a17s , other gabaergic amacrine cells that contact rbcs also express cp - gluars , in addition to ca - impermeable gluars ( chvez et al . , 2010 ) . by contrast , glycinergic amacrine cells that contact rbcs are driven by a combination of ca - impermeable gluars and nmda receptors ( glunrs ; chvez and diamond , 2008 ) . it is tempting to speculate that gabaergic , typically wide - field amacrine cells express cp - gluars and glycinergic , typically narrow - field amacrine cells express glunrs . aiis , glycinergic cells that express cp - gluars synaptically ( singer and diamond , 2003 ) and glunrs extrasynaptically ( hartveit and veruki , 1997 ) , would be a notable exception to that tentative rule . provide reciprocal gabaergic feedback to rbc terminals ( hartveit , 1996 , 1999 ; singer and diamond , 2003 ; chvez et al . , 2006 ) that shapes visual signaling in the rod pathway ( nakatsuka and hamasaki , 1985 ; euler and masland , 2000 ; dong and hare , 2003 ) . a17 somata rest at the distal border of the ipl and project dozens of thin , unbranched dendrites deep into the ipl where they receive synaptic input from rbcs ( ellias and stevens , 1980 ; kolb and nelson , 1983 ; grimes et al . , 2010 ) . at the low end of the response range , gaba release from a17 synaptic varicosities occurs independently of cav channels , relying instead on cp - gluars for ca influx ( chvez et al . , cav channels are expressed on the varicosities , but their activation is limited by a ca - activated k conductance . stronger stimulation overwhelms this k conductance and recruits cav channels to trigger release ( grimes et al . , 2009 ) . the local coupling between cp - gluars and gaba release , along with the biophysical features of the a17 dendrites , enables the individual synaptic varicosities to operate independently ( grimes et al . , 2010 ) . aiis may rely on the relatively low affinity of cp - gluars , rather than their ca permeability , to accurately encode vigorous multivesicular release from rbc ribbon synapses ( singer et al . rbc ribbons can unload their entire readily releasable vesicle pool in just a couple of milliseconds , yet aii epscs encode this release linearly , suggesting that the postsynaptic cp - gluars are far from saturation ( singer and diamond , 2006 ) , likely a critical feature at an analog synapse . as in horizontal cells , cp - gluars in amacrine cells also undergo a light - dependent , developmental decrease in polyamine sensitivity ( osswald et al . , 2007 ) . the change in amacrine cells is short - lived , however , with polyamine sensitivity returning to pre - eye - opening levels in about 2  weeks ( figure 2b ) . an interesting exception occurs in aii dendrites occupying the off sublamina of the ipl , where cp - gluars remain polyamine - insensitive into adulthood ( osswald et al . , 2007 ; figure 2b ) . the molecular mechanisms and functional implications of these developmental changes , which can differ between regions within individual cells , remains a very interesting , unanswered question . cell death plays an essential role in retinal development and disease ( valenciano et al . , 2009 ) . during the first 6  months of life , the human retina loses about 70% of its gcs ( valenciano et al . , 2009 ) , and similar losses occur in the rat during the first two postnatal weeks ( galli - resta and ensini , 1996 ) . in the adult retina , glaucoma , the most common cause of irreversible blindness , can claim 50% of the gc population ( kisiswa et al . , 2010 ) . as described below , recent work has implicated cp - gluars in both apoptosis and excitotoxicity and has identified cellular mechanisms that may regulate the expression of cp - gluars in the postsynaptic membrane . the coincidence in cp - gluar activity and gc cell death in the neonatal rat retina ( rorig and grantyn , 1993 ; leinders - zufall et al . , 1994 ; zhang et al . , 1995 ; otori et al . , 1998 ) suggests a potentially causal relationship between the two . one possibility is that increased cp - gluar activation in the retina might trigger intracellular signals that impair the gc s ability to compete for trophic factors at its axon terminals in the thalamus during this period of  neurotrophic cell death consistent with this scenario , cp - gluar activation induces neurite retraction and eventual cell death in gcs in neonatal rat ( otori et al . , 1998 ) and embryonic chick ( allcorn et al . , 1996 ; catsicas et al . , 2001 ) . while these reports indicated that cp - gluars initiate these processes , in mouse retina glunrs expressed by mller glial cells trigger expression of cp - gluars and cell death in gcs through nuclear factor b - mediated production of tumor necrosis factor  ( lebrun - julien et al . , interestingly , rat gcs cultured in the absence of mller glia are relatively resistant to nmda excitotoxicity , despite ample expression of glunrs ( ullian et al . , 2004 ) . moreover , not all gcs may be equally susceptible to cp - gluar - mediated toxicity : during the neonatal period of cell death , rat gcs exhibit a bimodal pattern of cp - gluar activity : one group exhibits gluar responses with low ca permeability , while another group exhibits very high ca permeability , based on electrophysiology , ca imaging , and co staining ( rorig and grantyn , 1993 ; leinders - zufall et al . . correlations between cp - gluar function and specific gc subtypes have not yet been explored . cp - gluar activation leads to a reduction in cp - gluar efficacy ( allcorn et al . , 1996 ; aizenman et al . , 2002 ; santiago et al . , 2006 ) , suggesting that cp - gluar signaling may be controlled homeostatically . such negative self - regulation could occur via cp - gluar - triggered increases in glua2 protein expression , as shown in a cultured rat retina model of diabetic retinopathy ( santiago et al . , 2006 ) , or via activity - dependent increases in intracellular polyamine synthesis , like that induced in the tadpole optic tectum by visual stimulation ( aizenman et al . , 2002 ) . recent experiments in cultured and intact mouse retina provide evidence for a third scenario in which activity induces subunit specific changes in gluar trafficking to the cell surface ( xia et al . , 2006 , 2007 ) . in retinal neurons ( and elsewhere ) , surface expression of gluars is maintained by a dynamic balance between ongoing receptor exocytosis and exocytosis , a process known as  constitutive cycling ( xia et al . , 2006 ) . when endocytosis is blocked , the number of receptors on the cell surface increases due to ongoing exocytosis ; conversely , blocking exocytosis decreases surface expression . the extent to which either modification changes surface expression is an indication of the rate of constitutive cycling . xia et al . ( 2006 ) exploited this system to show that exogenous ampa or synaptic activity decreases gluar cycling , whereas the gluar antagonist cnqx increased cycling . cycling is regulated by physiological activity , as light deprivation increased cycling in on gcs and decreased cycling in off gcs . these changes were observed following just 8  h of light deprivation , suggesting that gluar trafficking is regulated during the 12-h light  dark cycle . further experiments indicated that cycling receptors contain gluar2 and that activity - induced decreases in cycling lead to an increase in surface gluar2-containing , ca - impermeable receptors ( xia et al . , 2007 ) . synaptic quiescence , conversely , causes a reduction in surface gluar2 and , therefore , an increase in the relative contribution of cp - gluars . these results provide a mechanistic basis for activity - dependent regulation of cp - gluars in retinal neurons and suggest that retinal synapses , contrary to conventional wisdom , may possess the capacity for long - term plasticity . this review highlighted recent work implicating cp - gluars in several aspects of retinal development , function , and disease . there is still much to learn , however , about the roles for synaptic cp - gluar signaling in visual processing , as well as the mechanisms regulating cp - gluar expression and trafficking in the retina . improved pharmacological tools ( magazanik et al . , 1997 ) , recently developed genetically encoded synaptic ca indicators ( dreosti et al . , 2009 ; tian et al . , 2009 ) , and optogenetic approaches ( greenberg et al . , the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
the retina transforms light entering the eye into a sophisticated neural representation of our visual world . 
 specialized synapses , cells , and circuits in the retina have evolved to encode luminance , contrast , motion , and other complex visual features . 
 although a great deal has been learned about the cellular morphology and circuitry that underlies this image processing , many of the synapses in the retina remain incompletely understood . 
 for example , excitatory synapses in the retina feature the full panoply of glutamate receptors , but in most cases specific roles for different receptor subtypes are unclear . in this brief review 
 , i will discuss recent progress toward understanding how ca2 + -permeable ampa receptors ( cp - gluars ) contribute to synaptic transmission and newly discovered forms of synaptic plasticity in the retina .