Interplay of Cell-Autonomous and Nonautonomous Mechanisms Tailors Synaptic Connectivity of Converging Axons In Vivo

Abstract

Summary Neurons receive input from diverse afferents but form stereotypic connections with axons of each type to execute their precise functions. Developmental mechanisms that specify the connectivity of individual axons across populations of converging afferents are not well-understood. Here, we untangled the contributions of activity-dependent and independent interactions that regulate connections of two input types providing major and minor input onto a neuron. Individual transmission-deficient retinal bipolar cells (BCs) reduced synapses with retinal ganglion cells (RGCs), but active BCs of the same type sharing the dendrite surprisingly did not compensate for this loss. Genetic ablation of some BC neighbors resulted in increased synaptogenesis by the remaining axons in a transmission-independent manner. Presence but not transmission of the major BC input also dissuades wiring with the minor input, and with synaptically-compatible but functionally-mismatched afferents. Cell-autonomous, activity-dependent and non-autonomous, activity-independent mechanisms thus together tailor connections of individual axons amongst converging inner retinal afferents.

Development of Dendritic Form and Function

“…This pruning falls into the genetically determined category, as manipulation of afferent activity does not alter it (Devaud et al 2003, Lin et al 2000. Neural activity can affect some aspects of RGC dendrite refinement (Bodnarenko et al 1995, Okawa et al 2014, Tian & Copenhagen 2003, but for the most part, IPL sublaminar targeting is not altered by manipulating neural activity (Kerschensteiner et al 2009; for a review, see Kay & Sanes 2013). Therefore, to understand dendrite targeting in these and other cell types throughout the brain, we need to understand genetically determined mechanisms linking cell fate and arbor morphology.…”

Illuminating the Multifaceted Roles of Neurotransmission in Shaping Neuronal Circuitry

“…Thus, ON and OFF bipolar cells do not compete for synapses in an activity-dependent manner, but transmission does regulate their connectivity. In fact, the number of synapses formed between bipolar cells and retinal ganglion cells is regulated by transmission autonomously on a cell-by-cell basis (Okawa et al, 2014). In transgenic lines in which TeNT is expressed in a sparse population of ON bipolar cells, synaptic connectivity with the ganglion cell is only reduced for the TeNT-expressing axon (Figure 2B).…”

“…In transgenic lines in which TeNT is expressed in a sparse population of ON bipolar cells, synaptic connectivity with the ganglion cell is only reduced for the TeNT-expressing axon (Figure 2B). Neighboring active axons of the same type that co-innervate the dendrite of the postsynaptic ganglion cell do not increase their synapse number or density (Okawa et al, 2014). Thus, in this circuit, even though a local imbalance of transmission from neighboring axons results in a differential synaptic distribution amongst the converging axons, there is no ‘takeover’ by the more active axons.…”

“…Tiling precludes overlap between axonal terminals of the same type of bipolar cells, and may explain why the Type 6 bipolar cells do not exhibit homosynaptic (same input type) activity-dependent competition. Instead, releasing bipolar cells from the tiling constraint upon ablation of a subset of bipolar cells causes the remaining axons to expand (Figure 4C) and increase synaptic contact with the ganglion cell (Okawa et al, 2014). Thus these axons are not intrinsically limited in their ability to acquire more synaptic territory.…”

“…However, ablation of large numbers of Type 6 bipolar cells results in an increase in synaptic density made by Type 7 axons on the A ON ganglion cell (Figure 4D). Physical loss of Type 6 axons may enable Type 7 axons to more readily overlap with the dendrites of the ganglion cell and form more synapses (Okawa et al, 2014). A second example comes from the zebrafish retina where UV and blue cones contact the same stretch of dendrite of the H3 horizontal cell; although the stereotypic wiring of this circuit is activity-regulated, there is no competition between the cone types (Yoshimatsu et al, 2014).…”