Abstract
Connexin36 (Cx36) constituent gap junctions (GJ) throughout the brain connect neurons into functional syncytia. In the retina they underlie the transmission, averaging and correlation of signals prior conveying visual information to the brain. This is the first study that describes retinal bipolar cell (BC) GJs in the human inner retina, whose function is enigmatic even in the examined animal models. Furthermore, a number of unique features (e.g. fovea, trichromacy, midget system) necessitate a reexamination of the animal model results in the human retina. Well-preserved postmortem human samples of this study are allowed to identify Cx36 expressing BCs neurochemically. Results reveal that both rod and cone pathway interneurons display strong Cx36 expression. Rod BC inputs to AII amacrine cells (AC) appear in juxtaposition to AII GJs, thus suggesting a strategic AII cell targeting by rod BCs. Cone BCs serving midget, parasol or koniocellular signaling pathways display a wealth of Cx36 expression to form homologously coupled arrays. In addition, they also establish heterologous GJ contacts to serve an exchange of information between parallel signaling streams. Interestingly, a prominent Cx36 expression was exhibited by midget system BCs that appear to maintain intimate contacts with bistratified BCs serving other pathways. These findings suggest that BC GJs in parallel signaling streams serve both an intra- and inter-pathway exchange of signals in the human retina.
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Acknowledgements
Supported by OTKA K105247 to B. V. and by the Hungarian Brain Research Program (KTIA_NAP_13-2-2015-0008) to B. V. This research was also supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP- 4.2.4.A/2–11/1-2012-0001 ‘National Excellence Program’ to B. V. The technical assistance of Zsuzsanna Vidra is gratefully appreciated. The authors are thankful to Wilhelm Koch providing the recoverin anibody.
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429_2016_1360_MOESM1_ESM.tif
Cx36 immunolabeling in the human inner retina. Cross section displays the distribution of Cx36 plaques (green) in the human retina. Nuclei of retinal neurons are revealed by DAPI (blue). Cx36 plaques are scattered throughout the IPL but they occur most frequently in the ON sublamina (strata 4 and 5). In addition, Cx36 plaques also display a local maximum in strata 1 and 2. Inset shows an enlarged area of the IPL. This higher magnification reveals faint punctate labels in the middle of the IPL (stratum 3) that are invisible at lower power magnification. Abbreviations: OPL—outer plexiform layer, INL—inner nuclear layer, IPL—inner plexiform layer, GCL—ganglion cells layer. Scale bar: 10 µm (TIF 1960 KB)
429_2016_1360_MOESM2_ESM.tif
Control immunohistochemistry experiments. Rotational control experiments were performed for immunohistochemical labels to validate colocalizations of Cx36 plaques with neuronal markers of this study. Colocalization of Cx36 plaques with dense CaR/CaB labeled AII amacrine cell processes in both the ON and OFF sublamina and sparse Rec+ flat midget BC axons in the OFF sublamina were selected to show that they occure considerably more often than chance. a Colocalization of Cx36 plaques was tested with CaR and CaB labels in IPL strata 1-2 by comparing the number of colocalizations in the original labels (left column) with those of single channel rotated pairs (see Methods). Colocalizations of Cx36 plaques with CaR/CaB labeled AII (magenta) and CaR + non-AII (blue) processes occurred more often prior channel rotation. In contrast, counts of non colocalizing plaques (black) were significantly higher following channel rotation. Examples of colocalization tests in original and rotated panels are shown under the corresponding columns. Blue and magenta circles display examples of colocalizing Cx36 puncta with the corresponding CaB or CaR/CaB labeled neuronal profiles. b Colocalization of Cx36 plaques was tested with CaR and CaB labels in IPL strata 4-5 by comparing the number of colocalizations in the original labels (left column) with those of single channel rotated pairs. Colocalizations of Cx36 plaques with CaR/CaB labeled AII (magenta) and CaR + non-AII (blue) processes occurred more often prior channel rotation. In contrast, counts of non colocalizing plaques (black) were significantly higher following channel rotation. Examples of colocalization tests in original and rotated panels are shown under the corresponding columns. Blue and magenta circles display examples of colocalizing Cx36 puncta with the corresponding CaB or CaR/CaB labeled neuronal profiles. c Colocalization of Cx36 plaques was tested with Rec labeled flad bidget BC axon terminals in IPL strata 1-2 by comparing the number of colocalizations in the original labels (left column) with those of single channel rotated pairs. Although most Cx36 plaques showed no colocalization with Rec+ processes (black) colocalization (magenta) occurred almost twice more often in normal images (left) than expected by chance (rotated images on the right) shown in unrotated and rotated pie diagram pairs, respectively. Examples of colocalization tests in original and rotated panels are shown under the corresponding columns. Magenta circles display examples of colocalizing Cx36 puncta with Rec labeled neuronal profiles. Position 1-3 reflects retinal locations where plaque counts were performed (TIF 17110 KB)
429_2016_1360_MOESM3_ESM.tif
Histograms exhibit numbers of colocalizing Cx36 plaques with Neurolucide reconstructed axons of flat midget BC (n=6), giant bistratified BC (n=11) and diffuse type 3 BC (n=8) cells. Values on the x axis represent the order of axonal braches where Cx36 plaques were located (for details see Table 3). High SD values (error bars over each column) suggest significant variability in the location of Cx36 plaques for all three BC subtypes. However, there is a clear tendency for Cx36 GJ to locate towards the terminal axon of flat midget BCs, whereas those colocalize with giant bistratified BC and diffuse type 3 BC axons display a mid-axonal preference (TIF 37 KB)
429_2016_1360_MOESM4_ESM.tif
Colocalization of Cx36 plaques with BC neurochemical markers in the human retina. a Histogram shows the coverage factors of neurochemical marker in the human retina. CaB and CaR displayed the highest coverage in both the OFF (white bars) and ON sublaminas (gray bars), whereas PKCα and Rec were less frequent and constrained to the ON and OFF sublaminas, respectively. Each column represents average coverage values of selected retinal areas of the same stack, error bars show SD values. b Cx36 colocalized with CaR and CaB most frequently throughout the IPL but displayed significantly less colocalizations with PV, PKCα and Rec. c Colocalizations of Cx36 puncta were weighed with coverage factors of each marker to reveal the relative probability of colocalizations versus chance. The histogram shows that contrary to low colocalizations of Cx36 and Rec labels, their weighed colocalization is the highest among all markers indicating a high probability of real colocalizations. Abbreviations: CaR—calretinin, CaB—calbindin, PV—parvalbumin, PKCα—protein kinase C alpha subunit, Rec—recoverin, str—stratum (TIF 25024 KB)
429_2016_1360_MOESM5_ESM.tif
Two hypotheses for the functionality of heterologous BC GJs in the mammalian retina. a Magnocellular diffuse type 3 BC and/or parvocellular flat midget BC cells (gray) receive inputs from cone photoreceptors (green arrow). Signal from these BCs then are passed to GC targets via conventional glutamatergic chemical synapses thereby creating GC center receptive field (RF). In addition, upon opening of heterologous BC GJs (orange GJ symbols) signals also flow to blue cone giant bistratified BCs that summate responses of many BCs to establish a uniform surround signals for small and/or large bistratified GCs of the blue signaling stream. b flat midget BCs and/or diffuse type 3 BC BC (gray) currents evoked by focal light stimuly at the center RF are transmitted to postsynaptic GCs via glutamatergic synapses. Upon opening of heterologous GJs (left panel, orange GJ symbols), however, some evoked current is sinked (green open arrow) by GJ coupled giant bistratified BCs (black BC) thereby impeding flat midget BC-to-midget and/or diffuse type 3 BC-to-parasol GC signaling. In this scenario only high amplitude flat midget BC and/or diffuse type 3 BC depolarizations (evoked by likely high contrast) can be translated to a midget and parasol GCs, respectively (yellow arrows). On the other hand, when light stimuli are spatially extended (right panel) a simultaneous depolarization of giant bistratified BCs and electrically coupled flat midget BC and/or diffuse type 3 BC cells occurs. When giant bistratified BCs are depolarized the current sinking mechanism is less effective (red open arrow), thus midget and parasol BCs can transmit much of their signals to the corresponding postsynaptic GCs (green arrows). Such mechanism could tune visual acuity to percieve small objects against high contrast background, and low contrasts are only translated to GC signals if they reach a certain size. Abbreviations: c – cone, cBC – cone bipolar cell, flat midget BC—flat midget bipolar, diffuse type 3 BC—diffuse bipolar 3, giant bistratified BC—giant bistratified bipolar, GC—ganglion cell (TIF 20427 KB)
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Kántor, O., Varga, A., Nitschke, R. et al. Bipolar cell gap junctions serve major signaling pathways in the human retina. Brain Struct Funct 222, 2603–2624 (2017). https://doi.org/10.1007/s00429-016-1360-4
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DOI: https://doi.org/10.1007/s00429-016-1360-4