Abstract
The C. elegans ortholog of mammalian calsyntenins, CASY-1, is an evolutionarily conserved type-I transmembrane protein that is highly enriched in the nervous system. Mammalian calsyntenins are strongly expressed at inhibitory synapses, but their role in synapse development and function is still elusive. Here, we report a crucial role for CASY-1 in regulating GABAergic synaptic transmission at the C. elegans neuromuscular junction (NMJ). The shorter isoforms of CASY-1; CASY-1B and CASY-1C, express and function in GABA motor neurons where they regulate GABA neurotransmission. Using pharmacological, behavioral, electrophysiological, optogenetic and imaging approaches we establish that GABA release is compromised at the NMJ in casy-1 mutants. Further, we demonstrate that CASY-1 is required to modulate the transport of GABAergic synaptic vesicle (SV) precursors through a possible interaction with the SV motor protein, UNC-104/KIF1A. This study proposes a possible evolutionarily conserved model for the regulation of GABA synaptic functioning by calsyntenins.
Highlights
A remarkable feature of the nervous system is the specific connections between neurons, which allows for orchestrated neural networks and circuitry of the brain
Despite the potential deregulation of GABA signaling in several neurological disorders, our understanding of the genetic factors that regulate GABAergic synaptic transmission has just started to evolve
We identify a role for a cell adhesion molecule, CASY-1, in regulating GABA signaling at the C. elegans neuromuscular junction (NMJ)
Summary
A remarkable feature of the nervous system is the specific connections between neurons, which allows for orchestrated neural networks and circuitry of the brain. Calsyntenins are type-I transmembrane proteins characterized by the presence of two cadherin-like tandem repeats, an LG/LNS domain in the extracellular region and an intracellular region that carries two kinesin light-chain binding domains [17, 18] All these regions are conserved in the three human Calsyntenin genes; clstn, clstn and clstn as well as in the sole C. elegans calsyntenin ortholog, casy-1. In Zebrafish, the extracellular cadherin domains of calsyntenins have been shown to mediate homophilic adhesion [35] Despite all these studies that have allowed us to understand the functions of calsyntenins, we are still far from elucidating the molecular and physiological underpinnings of this molecule
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