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. 1996 Nov 1;16(21):6807-29.
doi: 10.1523/JNEUROSCI.16-21-06807.1996.

Amino Acid Signatures in the Primate Retina

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Free PMC article

Amino Acid Signatures in the Primate Retina

M Kalloniatis et al. J Neurosci. .
Free PMC article

Erratum in

  • J Neurosci 1997 Jan 1;17(1):500-3

Abstract

Pattern recognition of amino acid signals partitions virtually all of the macaque retina into 16 separable biochemical theme classes, some further divisible by additional criteria. The photoreceptor-->bipolar cell-->ganglion cell pathway is composed of six separable theme classes, each possessing a characteristic glutamate signature. Neuronal aspartate and glutamine levels are always positively correlated with glutamate signals, implying that they largely represent glutamate precursor pools. Amacrine cells may be parsed into four glycine-dominated (including one glycine/GABA immunoreactive population) and four GABA-dominated populations. Horizontal cells in central retina possess a distinctive GABA signature, although their GABA content is constitutively lower than that of amacrine cells and shows both regional and sample variability. Finally, a taurine-glutamine signature defines Müller's cells. We thus have established the fundamental biochemical signatures of the primate retina along with multiple metabolic subtypes for each neurochemical class and demonstrated that virtually all neuronal space can be accounted for by cells bearing characteristic glutamate, GABA, or glycine signatures.

Figures

Fig. 1.
Fig. 1.
Glutamate (Glu) and GABA immunoreactivity (sample 571) 1–3 mm from the fovea. A, Glutamate immunoreactivity is found throughout the retina, with low levels in Müller’s cells, occasional conventional and displaced amacrine cells, horizontal cells, and the outer segments of photoreceptors. Note the two interstitial ganglion cells. The highest level of immunoreactivity is displayed by ganglion cells and their axons. Note the differential labeling of cones and rods.B, Distinctive GABA signals are present in conventional and displaced amacrine cells, all horizontal cells, and a bipolar cell subset. Note the GABA-immunonegative interstitial ganglion cells.OS, Outer segments; IS, inner segments;ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer;IPL, inner plexiform layer; GCL, ganglion cell layer; A, amacrine cells; B, bipolar cells; H, horizontal cells; dA, displaced amacrine cells; M, Müller’s cells;nfl, nerve fiber layer; iG, interstitial ganglion cells; rpe, retinal pigmented epithelium.
Fig. 2.
Fig. 2.
Glycine (Gly) immunoreactivity (sample 571) 1–3 mm from the fovea. Conventional amacrine cells are the predominant G+ class. Many bipolar cells also exhibit glycine immunoreactivity, mostly in the distal inner nuclear layer (INL), although some cells have their somas in the Müller’s cell layer. V, Blood vessel. Other abbreviations defined in legend to Figure 1.
Fig. 3.
Fig. 3.
Taurine (Tau) immunoreactivity (sample 571) 1–3 mm from the fovea (A) and (sample M328) 8–10 mm from the fovea (B).A, Photoreceptors display the highest level of immunoreactivity, followed by bipolar cells. Müller’s cell somas are indistinguishable from bipolar cells in the middle of the inner nuclear layer (INL); however, Müller’s cell end-feet traversing the nerve fiber layer are easily identified. Note that horizontal cells (H) display low taurine immunoreactivity, whereas ganglion cells (G) are immunonegative. B, In the far periphery, Müller’s cells dominate taurine labeling patterns in the inner nuclear and ganglion cell layers. Ganglion cells and some amacrine cells are immunonegative. G, Ganglion cells. Other abbreviations defined in legend to Figure 1.
Fig. 4.
Fig. 4.
Glutamine (Gln) immunoreactivity (sample 571) 1–3 mm from the fovea. A, Ganglion cell somas display the highest level of glutamine immunoreactivity, with virtually every retinal neuron showing some degree of labeling. Note the difference in labeling between rod and cone photoreceptors and the distinctive labeling of Müller’s cell somas in the inner nuclear layer (INL). B, Higher-powered photomicrograph showing the labeling pattern in the inner plexiform layer (IPL) and ganglion cell layer (GCL) and an interstitial ganglion cell. C, Müller’s cell end-feet traversing the nerve fiber layer show morphological characteristics similar to the taurine-labeled processes noted earlier. Abbreviations defined in legend to Figure 1.
Fig. 5.
Fig. 5.
Aspartate (Asp) immunoreactivity (sample 571) 1–3 mm from the fovea. Ganglion (G) cell somas and dendrites (den) display strong aspartate labeling. A diffuse labeling pattern is present throughout the retina. Abbreviations defined in legend to Figure 1.
Fig. 6.
Fig. 6.
Serine (Ser) immunoreactivity (sample 571) 1–3 mm from the fovea. Diffuse labeling is found throughout the retina, with ganglion cell cytoplasm (G), vessel contents, the nerve fiber layer, and the occasional amacrine cell (A) displaying moderately higher levels of immunoreactivity. Abbreviations defined in legend to Figure 1.
Fig. 7.
Fig. 7.
Serial sections (sample 571) 1–3 mm from the fovea labeled for glutamate (A) and GABA (B). Two examples are given of the differences in glutamate precursor pools in conventional γ+ amacrine cells (A1 and A2) and interstitial γ+ amacrine cells (iA1 andiA2). Two γ+ bipolar cells are also indicated. Abbreviations defined in legend to Figure 1.
Fig. 8.
Fig. 8.
Amino acid→rgb mappings from registered serial 250 nm sections of primate retina (sample 571) 1–3 mm from the fovea. A, EGγ→rgb;B, τQE→rgb. See text for discussion.
Fig. 9.
Fig. 9.
Theme map of the primate retina (sample 571) 1–3 mm from the fovea. The map color codes used in all theme maps are shown at bottom. Each cell class is defined by K-means clustering and exhibits DT ≥ 1.9, except where noted otherwise (see Materials and Methods). The inner plexiform layer (IPL) has been masked off and collapsed in this and other theme maps, because the resolution of serial 250 nm section pattern recognition is insufficient to classify processes in the IPL.White areas in the retina proper correspond to blood vessels. Holes in a single section or other artifacts were excluded from analysis. Abbreviations defined in legend to Figure 1.
Fig. 10.
Fig. 10.
Foveal serial sections (sample M328) labeled for glutamate (A), GABA (B), taurine (C), glycine (D), aspartate (E), and glutamine (F). AG Γ1 amacrine cell (A witharrow), an E4 ganglion cell (G witharrow), and an E1 bipolar cell (B witharrow) on the foveal edge are indicated. Note the disarray of the immunoreactivity in the inner nuclear layer (INL) near the foveal edge and the GABA processes in the foveal floor (identified by arrowheads in B). Hf, Henle’s fibers. Other abbreviations defined in legend to Figure1.
Fig. 10.
Fig. 10.
Foveal serial sections (sample M328) labeled for glutamate (A), GABA (B), taurine (C), glycine (D), aspartate (E), and glutamine (F). AG Γ1 amacrine cell (A witharrow), an E4 ganglion cell (G witharrow), and an E1 bipolar cell (B witharrow) on the foveal edge are indicated. Note the disarray of the immunoreactivity in the inner nuclear layer (INL) near the foveal edge and the GABA processes in the foveal floor (identified by arrowheads in B). Hf, Henle’s fibers. Other abbreviations defined in legend to Figure1.
Fig. 11.
Fig. 11.
Theme map (sample M328) of primate fovea (L) and at an eccentricity of 1 mm (R). Note the pale brown G Γ1 amacrine cells in the amacrine cell layer (one indicated by anarrowhead), the abundance of E5 ganglion cells, and what may be displaced horizontal cell somas (asterisks). The photoreceptor layer has been removed for clarity, and the inner plexiform layer has been masked as in Figure 9.
Fig. 12.
Fig. 12.
Serial sections of midperipheral primate retina (sample M328) at 4–6 mm eccentricity, consecutively labeled for taurine (A), GABA (B), glutamate (C), and glycine (D). Several theme groups based on pattern recognition classification are indicated, including X1 (X1) cells with their “null” signatures, G Γ1 amacrine cells (G1), Γ2 (G2), and Γ44) amacrine cells to highlight the distinctively higher glutamate signals of Γ2 cells (Γ2), G+ E2 (E2) and GE1 (E1) bipolar cells, τ+ G2 andτG1 amacrine cells, conventionalE4 (E4) ganglion cells, and a weakly γ+ E6 (E6) ganglion cell. AGΓ1 amacrine cell is also indicated.
Fig. 13.
Fig. 13.
The signature matrix for the central primate retina. The left column identifies the theme class, and the right column identifies the cell class. Amino acids are grouped in vertical columns: GABA (γ), glycine (G), glutamate (E), aspartate (D), glutamine (Q), and taurine (τ). Each column demonstrates the distribution of a single amino acid across all theme classes, and each row is the univariate signature for each class. All probability density distributions are amplitude-normalized; the ordinate denotes the relative spectral density along an abscissa of increasing relative log amino acid concentration. Histograms were FFT-filtered to yield a resolution of ∼16 Hz, i.e., 16 unique concentration levels in 0.125 log unit steps in discrete terms. Signals with means ≤ −1 log units relative concentration are not included. BC, Bipolar cell;GC, ganglion cell; AC, amacrine cell;HC, horizontal cell; MC; Müller’s cell.
Fig. 14.
Fig. 14.
Bivariate and trivariate scatterplots of theme class amino acid signals. A, Glycine versus taurine distribution for the G theme class, demonstrating the nearly univariate separation of G2 (cyan) cells fromG1 (yellow) and G3(purple) cells. Conversely, no univariate signal statistically separates G1 and G3 cells, but they do separate in N-space because of signal covariance within a class. The points are subsets of all the data points from G cells in retina at 1–3 mm eccentricity, and the ellipses represent the 2 SD bounds of the distributions. B, The coherent distribution of glutamate, aspartate, and glutamine signals from various Eand G cells. Sample points from each theme class are denoted as various colors (E1′, E2, and E4cells as various yellows; E1 and E2′cells as blues; E3 cells as magenta; and G1 cells as green). Although it is not possible to sort out the groupings, the important point is the apparent monotonic relationships along the glutamate/glutamine and glutamate/aspartate dimensions. A detailed dissection of some of these groups is shown in Figures 15 and 16.
Fig. 15.
Fig. 15.
Bivariate single class 2 SD ellipses demonstrating the monotonic relationship between glutamate and aspartate levels across type E cells. Note the downward displacement of the E1 bipolar cells (and photoreceptors) from the trend and the upward displacement of T1Müller’s cells to slightly higher aspartate levels than expected based on their low basal glutamate content. Abbreviations defined in legend to Figure 13.
Fig. 16.
Fig. 16.
Bivariate single class 2 SD ellipses of glutamate and glycine signals across type E and G cells. In particular, note the stratification of cells into low glycine and high glycine regimes and the separations of E2 and E2′bipolar cells into two modes. Abbreviations defined in legend to Figure13.

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