Protocadherin-dependent dendritic self-avoidance regulates neural connectivity and circuit function

Dimitar Kostadinov,Joshua R Sanes

doi:10.7554/elife.08964

Abstract

Dendritic and axonal arbors of many neuronal types exhibit self-avoidance, in which branches repel each other. In some cases, these neurites interact with those of neighboring neurons, a phenomenon called self/non-self discrimination. The functional roles of these processes remain unknown. In this study, we used retinal starburst amacrine cells (SACs), critical components of a direction-selective circuit, to address this issue. In SACs, both processes are mediated by the gamma-protocadherins (Pcdhgs), a family of 22 recognition molecules. We manipulated Pcdhg expression in SACs and recorded from them and their targets, direction-selective ganglion cells (DSGCs). SACs form autapses when self-avoidance is disrupted and fail to form connections with other SACs when self/non-self discrimination is perturbed. Pcdhgs are also required to prune connections between closely spaced SACs. These alterations degrade the direction selectivity of DSGCs. Thus, self-avoidance, self/non-self discrimination, and synapse elimination are essential for proper function of a circuit that computes directional motion.

Highlights

The geometry of a neuron’s dendritic and axonal arbors is believed to be a major determinant of the neuron’s role within a circuit
We mated Chatcre mice to lines that express Cre-dependent fluorescent reporters (Buffelli et al, 2003; Madisen et al, 2010), identified starburst amacrine cells (SACs) in explants, and recorded from pairs of ON SACs shortly after eye opening and in young adults (P40-100) (Figure 2A)
We refer to wild-type SACs as Pcdhg22 SACs, since they have their full complement of Pcdhgs

Summary

Introduction

The geometry of a neuron’s dendritic and axonal arbors is believed to be a major determinant of the neuron’s role within a circuit. Other cases are more conjectural, and in very few cases have experiments attempted to make a causal link between particular dendritic geometries and neuronal function. We address this issue by analyzing a retinal direction-selective circuit. Dendrites of olfactory projection neurons and axons of mushroom body neurons exhibit self-avoidance in Drosophila (Wang et al, 2002a; Zhan et al, 2004; Hattori et al, 2007). Several cell-surface proteins have been implicated in self-avoidance, including Dscam, Turtle, Flamingo, LAR-like receptor tyrosine phosphatase, Unc-5, Unc-6 (Netrin), and Unc-40

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Results

Conclusion