Kainate Activation of Horizontal, Bipolar, Amacrine, and Ganglion Cells in the Rabbit Retina ROBERT E. MARC* John Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah 84132 ABSTRACT Patterns of excitation in populations of retinal bipolar, amacrine, and ganglion cells were mapped by activating -amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA) and kainate (KA) receptors with KA in the presence of the channel-permeant guanidinium analogue 1-amino-4-guanidobutane (AGB). Registered serial thin sections were probed with immunoglobulins targeting AGB, glutamate, glycine, and -aminobutyric acid (GABA) to visualize KA-evoked responses and the neurochemical signatures of distinct cell types. OFF-center cone bipolar cells and both type A and type B horizontal cells were strongly activated by KA. ON-center cone bipolar cells displayed weak AGB signals that arose at least partially, if not entirely, from coupling with KA-responsive glycinergic amacrine cells, whereas rod bipolar cells exhibited no detectable AGB permeation after KA activation. GABA-positive amacrine cells displayed a range of KA responses, some possessing little AGB signal even after strong KA activation, whereas all identifiable glycine-positive amacrine cells were driven by KA. Quantitative agonist responsivities of cells in the ganglion cell layer revealed that starburst amacrine cells are the most KA-responsive cell type in that layer. Ganglion cells varied in KA responsivity across morphologic subtypes, with a large -like ganglion cell group the being the most KA responsive. Some ganglion cells displayed weak KA responses, even with saturating doses, that may have been be due to an absence of AMPA/KA receptors or to the existence of AGB-impermeant AMPA/KA receptor complexes. J. Comp. Neurol. 407:65–76, 1999.  1999 Wiley-Liss, Inc. Indexing terms: -amino-3-hydroxyl-5-methylisoxazole-4-propionic acid receptors; kainate receptors; glycine; -aminobutyric acid The organic cation 1-amino-4-guanidobutane (AGB) per- meates ion channels activated by glutamate binding, and its accumulation in activated neurons can be detected immunocytochemically. Different types of retinal neurons appear to express varied mixtures of -amino-3-hydroxyl- 5-methylisoxazole-4-propionic acid (AMPA), kainic acid (KA), and N-methyl-D-aspartate (NMDA) receptors, and these mixtures may influence stimulus detection thresh- olds and visual response dynamic ranges. Many more retinal cell types have been described by using anatomical techniques than by using physiological techniques, and detailed comparisons of responses activated by glutamate agonists across comprehensive populations of cell types are not available. This report demonstrates that KA- evoked responses of mixed neuronal populations can be analyzed within single preparations, revealing differences in KA effectiveness across cell types and homogeneous responses within cell types. The rigid glutamate analogue KA activates AMPA recep- tors in a nondesensitizing mode and activates KA recep- tors with rapid desensitization (Lerma et al., 1993; Pater- nain et al., 1995). Because AGB permeation reports the integrated entry of cations through an activated channel, its signal will disproportionately reveal AMPA receptors, although bona fide KA receptors are known to exist in the vertebrate retina (Hughes et al., 1992; Mu ¨ ller et al., 1992; Morigawa et al., 1995; Peng et al., 1995; Brandsta ¨tter et al., 1997). Even with this bias toward nondesensitizing activations, differences in the ability of KA to trigger AGB permeation in different cell types reveals that their gluta- mate receptor mixtures cannot be identical. To make the case that a response reveals differences across cell types, one must demonstrate that at least some Grant sponsor: National Institutes of Health; Grant number: EY02576. *Correspondence to: Robert E. Marc, John Moran Eye Center, University of Utah School of Medicine, 75 N. Medical Drive, Salt Lake City, UT 84132. E-mail: robert.marc@hsc.utah.edu Received 20 February 1998; Revised 11 November 1998; Accepted 1 December 1998 THE JOURNAL OF COMPARATIVE NEUROLOGY 407:65–76 (1999)  1999 WILEY-LISS, INC.