Regulation of subcellular dendritic synapse specificity by axon guidance cues

Abstract

14Neural circuit assembly occurs with subcellular precision, yet the mechanisms underlying this 15 precision remain largely unknown. Subcellular synaptic specificity could be achieved by 16 molecularly distinct subcellular domains that locally regulate synapse formation, or by axon 17 guidance cues restricting access to one of several acceptable targets. We address these 18 models using two Drosophila neurons: the dbd sensory neuron and the A08a interneuron. In 19 wild-type larvae, dbd synapses with the A08a medial dendrite but not the A08a lateral dendrite. 20 dbd-specific overexpression of the guidance receptors Unc-5 or Robo-2 results in lateralization 21 of the dbd axon, which forms anatomical and functional monosynaptic connections with the 22A08a lateral dendrite. We conclude that axon guidance cues, not molecularly distinct dendritic 23 arbors, are a major determinant of dbd-A08a subcellular synapse specificity. 25Nervous system function is determined by the precise connectivity of neurons. From the 26 Drosophila larva with 10,000 neurons to the human with 80 billion neurons, all neurons are 27 faced with the challenge of identifying the correct subset of synaptic partners among many 28 potential target neurons. In addition to specificity at a cellular level, neural circuits also exhibit 29 synaptic specificity at the subcellular level (reviewed in Yogev and Shen, 2014). In Drosophila, 30

Establishment and Maintenance of Neural Circuit Architecture

“…For example, in the Drosophila ventral nerve cord (analogous to the vertebrate spinal cord), the segmentally repeated A08a interneuron has two spatially distinct dendritic arbors: one positioned medially and the other laterally. Many presynaptic neurons synapse with just the medial or lateral dendrite, but never both (Sales et al, 2019). Interestingly, the A02l and A31x neurons specifically target the lateral dendrite, but their projections arise contralaterally and they simply bypass the medial dendrite (Sales et al, 2019).…”

“…Many presynaptic neurons synapse with just the medial or lateral dendrite, but never both (Sales et al, 2019). Interestingly, the A02l and A31x neurons specifically target the lateral dendrite, but their projections arise contralaterally and they simply bypass the medial dendrite (Sales et al, 2019). Similarly, the dbd sensory neuron projects ipsilaterally from the periphery and bypasses the lateral dendrite to specifically synapse with the medial A08a arbor (Schneider-Mizell et al, 2016;Sales et al, 2019).…”

“…Interestingly, the A02l and A31x neurons specifically target the lateral dendrite, but their projections arise contralaterally and they simply bypass the medial dendrite (Sales et al, 2019). Similarly, the dbd sensory neuron projects ipsilaterally from the periphery and bypasses the lateral dendrite to specifically synapse with the medial A08a arbor (Schneider-Mizell et al, 2016;Sales et al, 2019). To determine how the dbd axon precisely targets the medial A08a dendritic arbor, Sales et al (2019) generated two hypotheses: either (1) secreted guidance cues directly steer the dbd axon to the medial arbor, precluding any interaction with the lateral arbor or (2) the two A08a dendritic arbors express distinct CAMs that make dbd competent to synapse onto the medial, but not the lateral, dendritic arbor.…”

“…Similarly, the dbd sensory neuron projects ipsilaterally from the periphery and bypasses the lateral dendrite to specifically synapse with the medial A08a arbor (Schneider-Mizell et al, 2016;Sales et al, 2019). To determine how the dbd axon precisely targets the medial A08a dendritic arbor, Sales et al (2019) generated two hypotheses: either (1) secreted guidance cues directly steer the dbd axon to the medial arbor, precluding any interaction with the lateral arbor or (2) the two A08a dendritic arbors express distinct CAMs that make dbd competent to synapse onto the medial, but not the lateral, dendritic arbor. The first hypothesis predicts that if dbd were redirected to the lateral arbor, it would form synapses at that location, whereas according to the second hypothesis, synapse formation would not occur because of incompatible cell-surface interactions.…”

Regulation of coordinated muscular relaxation by a pattern-generating intersegmental circuit

“…5d, e, g, and Supplementary Fig. 3d) 17,37,39,40 . GVLIs not only receive inputs from Canon neurons directly but also indirectly via A02l neurons, suggesting that these two second-order premotor neurons function in closely related circuits (Fig.…”