Abstract
In neural circuits, individual neurons often make projections onto multiple postsynaptic partners. Here, we investigate molecular mechanisms by which these divergent connections are generated, using dyadic synapses in C. elegans as a model. We report that C. elegans nrx-1/neurexin directs divergent connectivity through differential actions at synapses with partnering neurons and muscles. We show that cholinergic outputs onto neurons are, unexpectedly, located at previously undefined spine-like protrusions from GABAergic dendrites. Both these spine-like features and cholinergic receptor clustering are strikingly disrupted in the absence of nrx-1. Excitatory transmission onto GABAergic neurons, but not neuromuscular transmission, is also disrupted. Our data indicate that NRX-1 located at presynaptic sites specifically directs postsynaptic development in GABAergic neurons. Our findings provide evidence that individual neurons can direct differential patterns of connectivity with their post-synaptic partners through partner-specific utilization of synaptic organizers, offering a novel view into molecular control of divergent connectivity.
Highlights
Neurons are typically wired into discrete circuits through stereotyped patterns of synaptic connections geared to perform specific functions
Through a screen for genes that govern the formation of these divergent synaptic connections, we demonstrate that the synaptic organizer nrx-1/neurexin directs the outgrowth of previously uncharacterized dendritic spine-like structures and the formation of synaptic connections with GABAergic neurons, but is not required for synaptic connectivity with muscles
We found that cholinergic-specific expression of the nrx-1 locus encodes both long (nrx-1L) isoform significantly restored receptor clusters in the dendritic region of unc-3 animals (Figure 6G), indicating that the lack of ACR-12 receptor clusters in unc-3 mutants is largely driven by the absence of nrx-1 expression, additional phenotypes associated with mutation of unc-3 may contribute (Barbagallo et al, 2017)
Summary
Neurons are typically wired into discrete circuits through stereotyped patterns of synaptic connections geared to perform specific functions. Individual neurons within circuits may receive convergent synaptic inputs from multiple classes of presynaptic partnering neurons, and likewise, make divergent synaptic outputs onto distinct postsynaptic targets. The molecular processes controlling the establishment of divergent synaptic connections (between a single presynaptic partner and multiple postsynaptic target cells) are not clearly defined (Okawa et al, 2014b). Neural circuit models often represent divergent connections as a means for enabling the same signal from an individual presynaptic neuron to reach many different postsynaptic target cells. While molecular guidance cues directing axon outgrowth have been well-studied, an understanding of the molecular mechanisms responsible for directing target-specific connectivity has remained elusive
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