Dataset Information

UNC-43/CaMKII-triggered anterograde signals recruit GABA_ARs to mediate inhibitory synaptic transmission and plasticity at C. elegans NMJs.

ABSTRACT: Disturbed inhibitory synaptic transmission has functional impacts on neurodevelopmental and psychiatric disorders. An essential mechanism for modulating inhibitory synaptic transmission is alteration of the postsynaptic abundance of GABA_ARs, which are stabilized by postsynaptic scaffold proteins and recruited by presynaptic signals. However, how GABAergic neurons trigger signals to transsynaptically recruit GABA_ARs remains elusive. Here, we show that UNC-43/CaMKII functions at GABAergic neurons to recruit GABA_ARs and modulate inhibitory synaptic transmission at C. elegans neuromuscular junctions. We demonstrate that UNC-43 promotes presynaptic MADD-4B/Punctin secretion and NRX-1α/Neurexin surface delivery. Together, MADD-4B and NRX-1α recruit postsynaptic NLG-1/Neuroligin and stabilize GABA_ARs. Further, the excitation of GABAergic neurons potentiates the recruitment of NLG-1-stabilized-GABA_ARs, which depends on UNC-43, MADD-4B, and NRX-1. These data all support that UNC-43 triggers MADD-4B and NRX-1α, which act as anterograde signals to recruit postsynaptic GABA_ARs. Thus, our findings elucidate a mechanism for pre- and postsynaptic communication and inhibitory synaptic transmission and plasticity.

SUBMITTER: Hao Y

PROVIDER: S-EPMC10015018 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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UNC-43/CaMKII-triggered anterograde signals recruit GABAARs to mediate inhibitory synaptic transmission and plasticity at C. elegans NMJs.

Hao Yue Y Liu Haowen H Zeng Xian-Ting XT Wang Ya Y Zeng Wan-Xin WX Qian Kang-Ying KY Li Lei L Chi Ming-Xuan MX Gao Shangbang S Hu Zhitao Z Tong Xia-Jing XJ

Nature communications 20230315 1

Disturbed inhibitory synaptic transmission has functional impacts on neurodevelopmental and psychiatric disorders. An essential mechanism for modulating inhibitory synaptic transmission is alteration of the postsynaptic abundance of GABAARs, which are stabilized by postsynaptic scaffold proteins and recruited by presynaptic signals. However, how GABAergic neurons trigger signals to transsynaptically recruit GABAARs remains elusive. Here, we show that UNC-43/CaMKII functions ...[more]

PMID: 36918518

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Project description:BackgroundThe conserved Caenorhabditis elegans proteins NID-1/nidogen and PTP-3A/LAR-RPTP function to efficiently localize the presynaptic scaffold protein SYD-2/?-liprin at active zones. Loss of function in these molecules results in defects in the size, morphology and spacing of neuromuscular junctions.ResultsHere we show that the Cav2-like voltage-gated calcium channel (VGCC) proteins, UNC-2 and UNC-36, and the calmodulin kinase II (CaMKII), UNC-43, function to regulate the size and morphology of presynaptic domains in C. elegans. Loss of function in unc-2, unc-36 or unc-43 resulted in slightly larger GABAergic neuromuscular junctions (NMJs), but could suppress the synaptic morphology defects found in nid-1/nidogen or ptp-3/LAR mutants. A gain-of-function mutation in unc-43 caused defects similar to those found in nid-1 mutants. Mutations in egl-19, Cav1-like, or cca-1, Cav3-like, ?1 subunits, or the second ?2/? subunit, tag-180, did not suppress nid-1, suggesting a specific interaction between unc-2 and the synaptic extracellular matrix (ECM) component nidogen. Using a synaptic vesicle marker in time-lapse microscopy studies, we observed GABAergic motor neurons adding NMJ-like structures during late larval development. The synaptic bouton addition appeared to form in at least two ways: (1) de novo formation, where a cluster of vesicles appeared to coalesce, or (2) when a single punctum became enlarged and then divided to form two discrete fluorescent puncta. In comparison to wild type animals, we found unc-2 mutants exhibited reduced NMJ dynamics, with fewer observed divisions during a similar stage of development.ConclusionsWe identified UNC-2/UNC-36 VGCCs and UNC-43/CaMKII as regulators of C. elegans synaptogenesis. UNC-2 has a modest role in synapse formation, but a broader role in regulating dynamic changes in the size and morphology of synapses that occur during organismal development. During the late 4th larval stage (L4), wild type animals exhibit synaptic morphologies that are similar to those found in animals lacking NID-1/PTP-3 adhesion, as well as those with constitutive activation of UNC-43. Genetic evidence indicates that the VGCCs and the NID-1/PTP-3 adhesion complex provide opposing functions in synaptic development, suggesting that modulation of synaptic adhesion may underlie synapse development in C. elegans.

Dataset Information

UNC-43/CaMKII-triggered anterograde signals recruit GABA_ARs to mediate inhibitory synaptic transmission and plasticity at C. elegans NMJs.

Publications

UNC-43/CaMKII-triggered anterograde signals recruit GABA<sub>A</sub>Rs to mediate inhibitory synaptic transmission and plasticity at C. elegans NMJs.

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