Abstract
The first synapse of the visual pathway is formed by photoreceptors, horizontal cells and bipolar cells. While ON bipolar cells invaginate into the photoreceptor terminal and form synaptic triads together with invaginating horizontal cell processes, OFF bipolar cells make flat contacts at the base of the terminal. When horizontal cells are ablated during retina development, no invaginating synapses are formed in rod photoreceptors. However, how cone photoreceptors and their synaptic connections with bipolar cells react to this insult, is unclear so far. To answer this question, we specifically ablated horizontal cells from the developing mouse retina. Following ablation around postnatal day 4 (P4)/P5, cones initially exhibited a normal morphology and formed flat contacts with OFF bipolar cells, but only few invaginating contacts with ON bipolar cells. From P15 on, synaptic remodeling became obvious with clustering of cone terminals and mislocalized cone somata in the OPL. Adult cones (P56) finally displayed highly branched axons with numerous terminals which contained ribbons and vesicular glutamate transporters. Furthermore, type 3a, 3b, and 4 OFF bipolar cell dendrites sprouted into the outer nuclear layer and even expressed glutamate receptors at the base of newly formed cone terminals. These results indicate that cones may be able to form new synapses with OFF bipolar cells in adult mice. In contrast, cone terminals lost their invaginating contacts with ON bipolar cells, highlighting the importance of horizontal cells for synapse maintenance. Taken together, our data demonstrate that early postnatal horizontal cell ablation leads to differential remodeling in the cone pathway: whereas synapses between cones and ON bipolar cells were lost, new putative synapses were established between cones and OFF bipolar cells. These results suggest that synapse formation and maintenance are regulated very differently between flat and invaginating contacts at cone terminals.
Highlights
At the visual system’s first synapse, cone photoreceptors provide synaptic input to horizontal cells, ON bipolar cells and OFF bipolar cells, thereby splitting the light information into parallel pathways
We used Cx57+/diphtheria toxin receptor (DTR) mice that selectively express the DTR from primates selectively in horizontal cells (Sonntag et al, 2012) and induced an apoptosis of horizontal cells by the injection of DT at postnatal day 4 (P4) and P5 (Nemitz et al, 2019)
Cone synaptogenesis has just started and cone terminals begin to form the first contacts with horizontal cells (Sherry et al, 2003)
Summary
At the visual system’s first synapse, cone photoreceptors provide synaptic input to horizontal cells, ON bipolar cells and OFF bipolar cells, thereby splitting the light information into parallel pathways. Two different types of contacts can be distinguished at the cone terminal: Invaginating contacts with horizontal and ON bipolar cells (triads) and flat contacts with OFF bipolar cells (Haverkamp et al, 2000). Starting at P6, this dendrite invaginates into the cone pedicle together with a second horizontal cell dendrite and both horizontal cell processes are positioned lateral to the ribbon. Between P7 and P10, triads are completed by the addition of one or two ON bipolar cell dendrites that occupy the central position below the synaptic ribbon
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