A diversity of GABA receptors in the retina

seminarsin CELL & DEVELOPMENTAL BIOLOGY, Vol9, 1998: p p 293-299

Article Number: sr980238

A diversity of GABA receptors in the retina Peter D. Lukasiewicz and Colleen R. Shields

GABA, a major inhibitory transmitter in the vertebrate retina, plays important roles in processing visual information. There are three functional families of retinal GABA receptors, the ionotropic GABAA and GABA, receptors and the metabotropic GABA, receptor. GABA, receptors are enriched in the retina, compared to other parts of the CNS. GABA, and GABA, receptors are found on subsets of neurons, whereas GABAA receptors are ubiquitous. The distinct functional properties of GABAA , GABA, and GABA, receptors suggests that individual neurons with different receptor complements have unique responses to GABA. Key words: GABA, receptor / GABA, receptor / GABA, receptor / retina / visual processing

01998 Academic Press

GABA IS AN IMPORTANT inhibitory transmitter in the retina as well as in other parts of the central nervous system. In the retina, GABA-mediated inhibition may play important roles in modulating visual information as it flows from photoreceptors to the brain. The retina possesses three types of GABA receptors, GABAA, GABAB and GABA,. GABAA and GABAB receptors are found widely in the CNS, but the GABA, receptor has a narrower distribution.' GABA, receptors are found mainly in the retina, but are also located in select areas of the brain.'-4 Because of the diversity of GABA receptors in the retina, inhibitory responses in individual neurons may be shaped by distinct populations of GABA receptors.

Pharmacological and molecular characteristics of GABA receptors GABA receptors have been traditionally classified into two distinct types, the ionotropic GABA A receptors and the metabotropic GABAB receptor^.^ These two classes of receptors are functionally, molecularly and pharmacologically different. GABAA receptors are pentameric, ligand-gated ion channels composed of different subunits (e.g. a , p , y , 8) which are highly permeable to chloride.6 Bicuculline and picrotoxin are antagonists at GABAA receptors, whereas barbiturates and benzodiazepines potentiate GABAA receptor function. GABAB receptors, in contrast, which couple with G-proteins, are insensitive to GABAA receptor antagonists. G-protein activation by GABA receptors opens postsynaptic potassium channels or reduces pre- and postsynaptic voltage-gated calcium channel current^.^*^ GABA receptors have been recently cloned and they consist of a single polypeptide that is similar in sequence to metabotropic glutamate receptor~.~ GABA, receptors form a third, novel class of receptors. These ionotropic receptors are insensitive to potentiation by barbiturates or benzodiazepines. GABA receptors are also insensitive to the GABA, agonist baclofen and the GABAA antagonist b i c ~ c u l l i n e , ~ however, ~'~ they are sensitive to blockade by picrotoxin or 3-aminopropyl(methy1)phosphonic acid (3-APMPA) (Figure l).' 5 2' 6 GABA, receptors are thought to be composed exclusively of p subunits.'*17The p l subunit, first cloned from human retina, has only 30-38% amino acid similarity to the a , p , y , S GABAA subunits.' The GABAA subunits themselves share only 29-39% amino acid identity.6 The p2 and p3 subunits have also been cloned from the retina and they share 74 and 63% amino acid homology with the p l subunit, respe~tively.'~~'~ While GABA A receptors are het-

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From the *Departments of Ophthalmology and Visual Science and Anatomy and Neurobiology, Washington University School of Medicine, Box 8096, St. Louis, MO 63110, USA 01998Academic Press 1084-9521/ 98/ 030293+ 07 $30.00/ 0

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eromeric pentamers, GABA, receptors probably exist either as homomeric receptors composed of p 1 subunits' or as heteromeric channels composed of p l and p2 subunits?.20 It is still unclear how p l , p2 and p3 subunits may combine to form native GABA, receptors, but the diversity of subunits suggests the existence of additional subtypes of GABA receptors. For example, most GABA, receptors are blocked by picrotoxin, however, those on rat bipolar cells are relatively insensitive to this antag~nism."~'~ The picrotoxin insensitivity in rat bipolar cells is due to a single amino acid substitution in the p2 subunit?'

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Figure 1. (A) GABAA receptors mediate the early part of the response to a 20-ms puff of GABA, while GABA, receptors mediate the later part of the response. The pharmacological dissection of a ferret bipolar cell GABA response indicates that the time courses of GABAA and GABA receptor-mediatedcurrents are different. Current responses to GABA (200 p M ) puffed onto ferret bipolar cell axon terminals were recorded in the retinal slice preparation using whole cell patch clamping. This is a putative OFF, cone bipolar, identified by Lucifer-yellow staining. The early part of the response was reduced by bicuculline (200 pM), but the later part of the response was unaffected. The bicuculline-insensitivecurrent had a prolonged time course and was blocked by S-aminopropyl(methy1)phosphonic acid (3-APMPA),indicating that it was mediated primarily by GABA, receptors. (B) The later part of the GABA response was reduced by 3-APMPA (300 pM), but the early part of the response was unaffected. The 3-APMPA-resistant current had a transient time course and was blocked by bicuculline, indicating that it was mediated primarily by GABAA receptors. The cell was voltageclamped to - 60 mV and the calculated ECl was 0 mV. Strychnine, 2-amino-5-phosphonopentanoicacid and 6cyano-7-nitroquinoxaline-2,3-dione (CNQX) were included in the control solution to block glycine and glutamate receptors. The duration of the puff is indicated by the bars above the responses.

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Although GABAA and GABA, receptors both gate chloride channels, these two classes of receptors are functionally distinct. These receptors have different sensitivities to GABA; GABA, receptors have approximately a 10-fold higher sensitivity than GABAA receptors [Figure 2(A)].10,21 Similar differences in GABA sensitivity have been observed in cloned and expressed p and GABAA receptor subunit^.^^-^^ The receptors increased GABA sensitivity of p 1/GABA appears to be due to additional GABA binding sites, thereby increasing the likelihood that the channel will open.25 Homomeric p l receptors contain five GABA binding sites, whereas GABAA receptors have only two. GABAA receptor-mediated currents are transient whereas GABA receptor-mediated currents are relatively sustained following either brief or sustained applications of GABA (Figure 1).'o,'6,26Similar differences in response time courses are observed between p and GABAA subunits expressed in Xeno pus oocytes.22Figure 1 shows that the early phase of GABA responses in ferret bipolar cells is dominated by GABAA receptors, whereas the late phase is dominated by GABA, receptors. This suggests that the time course of inhibition is shaped by the complement of GABA receptors. Synaptic responses mediated mainly by salamander GABAA or GABA, receptors also show distinct time courses.27In response to brief electrical stimulation of amacrine cells, the GABA A receptor-dominated responses recorded in ganglion cells have rapid responses, whereas the GABA receptor-dominated responses in bipolar cells have prolonged responses, indicating that GABA receptor subtypes contribute to the time course of the synaptic re~ponse.'~The desensitization of GABAA

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receptors, however, may not solely determine the time course of IPSCs (inhibitory postsynaptic currents), because GABA receptor desensitization is slow (T 1 s)'03z8compared to the decay of GABAA receptor-mediated IPSCs (T 30 ms).'8 Additional factors, therefore probably contribute to the different responses. The slower deactivation of p l subunit receptors compared to GABAA receptors may contribute to longer response duration." Additionally, the extra binding sites on thepl subunit receptors may increase the stability of the open state conformati~n?~ leading to prolonged responses. Differences in the durations of GABA, and GABA, receptor-mediated synaptic responses have also been described. GABA A receptor-mediated chloride responses are brief and GABA receptor-mediated potassium responses are p r o l ~ n g e d . ~ ~ . ~ ~ reGABAA ceptors are activated with weaker stimulus intensities than are GABAB receptors, even though these receptors have roughly the same affinity for GABA." This discrepancy in sensitivity has led some to postulate that GABAA receptors may be synaptic while GABAB receptors may be e x t r a s y n a p t i ~ . ~ ~ ~ ~ ~

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Locations of GABA receptors in retina As visual signals pass through the retina from the photoreceptors, through bipolar cells to the ganglion cells, they are modified by synaptic inputs from horizontal cells and amacrine cells, which are GABAergic interneurons?' Horizontal cells form synaptic contacts with photoreceptor axon terminals and bipolar cell dendrites at the outer plexiform layer (OPL). Amacrine cells form synaptic contacts with bipolar cell axon terminals and ganglion cell dendrites at the inner plexiform layer (IPL). Because different classes of GABA receptors have distinct properties, the complement of GABA receptors at a given retinal synapse may shape the synaptic response of the postsynaptic cell. GABAA receptors are found on almost every type of neuron in the retina and they are both pre- and postsynaptic?' This class of receptor probably exists in the retina in a variety of subtypes that have different subunit compositions and retinal 10cations.3~For example, benzodiazepine binding sites are associated with GABAA receptors located in the IPL but not the OPL of ~ a l a m a n d e r .Receptor ~~ localization studies indicate that GABAA receptors of more than one subunit composition may be present on a single ganglion cell. Antibodies specific for distinct a subunits

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showed that the different subtypes are not colocalized to the same receptor clusters, indicating that different types of GABAA receptors are concentrated at particular synaptic sites.35Physiological studies are still needed, however, to determine whether different functional properties are associated with these distinct GABAA receptor subtypes. GABA, receptors, by contrast, are found only on some classes of retinal neurons. Physiological and pharmacological studies indicate that, in most species, GABA, receptors are present mainly on bipolar cells, primarily at their axon terminals, where they are often colocalized with GABAA receptors [Figure 2(B)].11-13,26,36 Some horizontal cells in fish",37 but not in amphibians and mammal^^^.^^ have GABA receptors. Both immunocytochemical a n d in situ hybridization studies support these GABA receptors have been reported to underlie a small fraction of GABA responses in ganglion cells in ~alamander.~'Most physiological evidence, however, indicates that GABA-mediated chloride currents are through GABAA receptors in ganglion and amacrine cells [Figure 2(B)]."-'3,16 Rat and chick amacrine and ganglion cells have p 2 subunit but no protein has been and no evidence for GABA, receptor mediated currents has been found.13 Taken together, these data indicate that, in most species, GABA, receptors are located presynaptic to ganglion cells on retinal bipolar cell axon terminals. GABA receptors are found postsynaptically on amacrine and ganglion cells.44In addition, subtypes of salamander and goldfish bipolar cells possess presynaptic GABA, receptor^.^^.^^ Electrophysiological studies indicate that different classes of neurons have different types of GABAB receptors. Some GABA, receptors are activated by b a c l ~ f e nand ~~,~~ others are insensitive to b a c l ~ f e n . Ganglion ~ ~ . ~ ~ cells have baclofen-sensitive GABA receptors that activate a potassium c o n d ~ c t a n c eand ~ ~ suppress N-type calcium channel currents.47 Bipolar and ganglion cells have baclofen-insensitive GABA receptors that are activated by CACA (cis-aminocrotonic acid) and suppress L-type calcium channel currents.46247 Further work is needed to determine the roles of GABA receptors in retinal processing.

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The roles of GABA receptors at the inner plexiform layer Ganglion cell receptive fields are organized into con-

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Figure 2. (A) Concentration-response relationships of GABA A and GABA receptors. Curves are logistic functions that were generated using average EC,, and Hill coefficients reported in the l i t e r a t ~ r e . ~The ~ . ~EC,, ~.~~ values were 3 and 30 p M , respectively, for GABA, and GABAA receptors. The Hill coefficients were 1.5 and 1.7, respectively, for GABA, and GABAA receptors. (B) A schematic diagram of the IPL illustrating the pre- and postsynaptic locations of GABAA and GABA receptors. GABAergic amacrine cells make both pre- and postsynaptic contacts with bipolar terminals and ganglion cell dendrites, respectively. (C) Ganglion cell intensity-response relationships for the receptive field center measured in the absence and presence of surround illumination. Dim surrounds antagonized the center response, causing a parallel shift of the relationship. However, the antagonism could be overcome by increased center illumination. This is consistent with presynaptic inhibition mediated by GABA, and GABAA receptors on the bipolar cell, resetting the stimulus-transmitterrelease function. Bright surrounds antagonize the center response more, causing a further parallel shift and a compression of the relationship by decreasing the maximum response. This is consistent with direct inhibition mediated by GABAA receptors on the ganglion cells that cannot be surmounted by increased center illumination. Figure 2C was modeled after the work by Thibos and Werblin.” (D) Schematic of IPL illustrating the putative pre- and postsynaptic inhibitory surround pathways that may be activated by dim and bright surrounds, respectively.

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cell types because the relative contribution of GABA and GABA, receptors can vary with cell type.12,16.54 This suggests that particular retinal circuits that are subserved by distinct types of bipolar cells (e.g. on versus off or rod versus cone) could be differentially shaped by GABAergic synaptic i n p ~ t s . 5In ~ addition, the effectiveness of both GABA, and GABA, receptors can be modulated by substances like dopamine, somatostatin and VIP.55 Dopamine enhances GABA, currents55 and reduces GABA c ~ r r e n t s . ~ This ~.~~ alteration in receptor effectiveness may alter the GABA response properties of bipolar cells.

centric center and surround regions. Illumination of the surround region antagonizes responses activated by the center illumination. GABA receptors may mediate the lateral inhibition in the IPL that underlies, in part, the ganglion cell surround. Presynaptic but not postsynaptic inhibition in the IPL involves the highly sensitive GABA, receptor^.^' Thus, surroundmediated feedback to bipolar axon terminals should be more effective at low synaptic GABA concentrations than the surround-mediated feedforward inhibition to ganglion cell dendrites via GABA, receptors. The properties of surround responses in salamander ganglion cells depend on light intensity [Figure 2(C)].50Dim surrounds antagonize the responses to receptive field center illumination, but this antagonism can be overcome by increasing the receptive field center intensity. The parallel rightward shift of the ganglion cell center intensity-response function with dim surrounds is consistent with presynaptic inhibition at the bipolar terminals, i.e. reduced synaptic gain [Figure 2(C,D)1. Brighter surrounds also inhibit the responses to center illumination, but this antagonism can not be overcome by increasing the center intensity?' This resulted in an additional rightward shift of the response function and decreased the maximum response, consistent with direct inhibition of ganglion cells [Figure 2(C,D)1. Based on the properties of retinal GABA receptors, we can make the following conjectures. The more sensitive GABA, receptors on bipolar cell terminals are responsible, in part, for the reduced synaptic gain found with dim surrounds, while the less sensitive GABA, and GABA, receptors on ganglion and bipolar cells underlie additional synaptic gain reduction and the dynamic range compression found with brighter surrounds. Other lateral inhibitory pathways in the IPL that utilize GABA underlie motion and direction sen~itivity!~.~~~~' The types and locations of the GABA receptors involved in these pathways have not been worked out. GABA receptors may also be involved in local gain control circuitry, that is, to regulate the output of bipolar cells over a range of stimulus conditions. Negative feedback at reciprocal synapses between bipolar terminals and amacrine cells53could lead to reductions in synaptic noise and synaptic gain. The dynamic range of negative feedback would be larger for bipolar cell terminals with GABA, receptors, compared to those with just GABA, receptors, because they can respond to lower synaptic GABA concentrations. Responses to GABA would differ in distinct bipolar

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The roles of GABA receptors in the outer plexiform layer The antagonistic center-surround organization of the visual pathway first occurs at bipolar cells.58 Direct photoreceptor input to bipolar cells forms the center of the receptive field, while horizontal cells form the surround of the receptive field. GABAergic horizontal cells were thought to mediate surround inputs because they make presynaptic contacts with photoreceptors and postsynaptic contacts with bipolar cells.59Photoreceptor synaptic terminals have GABA receptors and respond to applied GABA," but bipolar cell dendrites exhibit little or no sensitivity to applied GABA."s~~GABA agonists or antagonists, however, do not affect surround responses in cones or bipolar cells,61362 suggesting that GABA receptors do not mediate bipolar cell surround inhibition. GABA receptors on horizontal cells modulate the kinetics of their light response^.^^,^^ Because the chloride equilibrium potential is positive to the resting potential in horizontal cells, GABA acts as an excitatory transmitter. GABA depolarization causes additional GABA release, activating a positive feedback loop that controls the kinetics and shape of the light response.

Summary The reasons for the diversity of retinal GABA receptors are still not fully understood. We do know, however, that the molecular and pharmacological characteristics of retinal GABA,, GABA and GABA receptors are distinct. Furthermore, different classes of GABA receptors have particular cellular locations in the retina. Finally, these separate classes of GABA receptors have different functional properties, sug-

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P.D.Lukasiweicz and C. R. Shields 13. Yeh HH, Grigorenko EV, Veruki ML (1996) Correlation between a bicuculline-resistantresponse to GABA and GABA, receptor p l subunit expression in single rat retinal bipolar cells. Vis Neurosci 13:283-292 14. Johnston GAR (1986) Multiplicity of GABA receptors. Recept Biochem Methodol 5:57-71 Pan Z-H, Lipton SA (1995) Multiple GABA receptor subtypes mediate inhibition of calcium influx at rat retinal bipolar cell terminals. J Neurosci 15:2668-2679 Lukasiewicz PD, Wong ROL (1997) GABAc receptors on ferret retinal bipolar cells; a diversity of subtypes in mammals? Vis Neurosci in press: Shimada S, Cutting G, Uhl GR (1992) y-Aminobutyric acid A or C receptor? gamma-yacid p l receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive yaminobutyric acid responses in Xenopus oocytes. Mol Pharmacol41:683-687 18. Wang Tian-L, Guggino WB, Cutting GR (1994) A novel y-aminobutyric acid receptor subunit (p2) cloned from human retina forms bicuculline-insensitive homooligomeric receptors in xenopus oocytes. J Neurosci 14:6524-6531 19. Ogurusu T, Shingai R (1996) Cloning of a putative yaminobutyric acid (GABA) receptor subunit p3 cDNA. Biochim Biophys Acta 1305:15-18 20. Zhang D, Pan Z-H, Zhang X, Brideau AD, Lipton SA (1995) Cloning of a y-aminobutyric acid type C receptor subunit in rat retina with a methionine residue critical for picrotoxin channel block. Proc Natl Acad Sci USA 92:11756-11760 21. Feigenspan A, Bormann J (1994) Differential pharmacology of GABA, and GABA, receptors on rat retinal bipolar cells. Eur J Pharmacol288:97-104 22. Amin J, Weiss DS (1994) Homomeric p l GABA channels: activation properties and domains. Recept Channels 2:227-236 23. Kusama T, Spivak CE, Whiting P, Dawson VL, Schaeffer JC, Uhl GR (1993) Pharmacology of GABA p l and GABA a/P receptors expressed in Xenopus oocytes and Cos cells. Br J Pharmacol 109:200-206 24. Polenzani L, Woodward RM, Miledi R (1991) Expression of mammalian y-aminobutyric acid recpetors with distinct pharmacology in Xenopus oocytes. Proc Natl Acad Sci USA 88:4318-4322 25. Amin J, Weiss DS (1996) Insights into the activation mechanism of p l GABA receptors obtained by coexpression of wild type and activation-impaired subunits. Proc R SOCLondon B 263:273-282 26. Qian H, Dowling JE (1995) GABAa and GABAc receptors on hybrid bass retinal bipolar cells. J Neurophysiol74: 1920-1928 27. Shields CR, Lukasiewicz PD (1996) Stimulation of amacrine cells elicits synaptic inputs to ganglion cells mediated by GABA, receptors. SOCNeurosci Abstr 22:881 28. Borst JGG, Lodder JC, Kits KS (1994) Large amplitude variability of GABAergic IPSCs in melanotropes from Xenopus laevis: Evidence that quanta1 size differs between synapses. J Neurophysiol71:639-655 29. Mody I, De Koninck Y, Otis TS, Soltesz I (1994) Bridging the cleft at GABA synapses in the brain. TINS 17:517-525 30. Misgeld U, Bijak M, Jarolimek W (1995) A physiological role for GABA, receptors and the effects of baclofen in the mammalian central nervous system. Prog Neurobiol 46:423-462 31. Dowling JE (1987) The Retina: an approachable part of the brain. The Belknap Press of Harvard University Press, Cambridge, MA 32. Lam DM-K (1997) Neurotransmitters in the vertebrate retina. Invest Ophthamol Vis Sci 38:553-556 33. Greferath U, Grunert U, Fritschy JM, Stephenson A, Mohler H, Wassle H (1995) GABA, receptor subunits have differen-

gesting that response properties of retinal neurons will be shaped by the complements of GABA receptors they express. For example, the distribution of ionotropic GABA receptors in the IPL suggests that presynaptic inhibition mediated by highly sensitive GABA, receptors on bipolar cells will be more effective than postsynaptic inhibition mediated by GABA, receptors on ganglion cells. Although some of the locations and functional properties of GABA receptors in the retina have been worked out, further research on their roles in retinal visual information processing is needed.

Acknowledgements We thank S. Bissen, M. Higgs, C. Romano and R. Wong for helpful comments on the manuscript. Supported by NIH grants EY08922 (PDL), EY07057 (CRS), EY02687, a Core Grant to the Dept. of Ophthalmology, Research to Prevent Blindness.

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