UNC-43/CaMKII-triggered anterograde signals recruit GABAARs 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 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 at GABAergic neurons to recruit GABAARs 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 GABAARs. Further, the excitation of GABAergic neurons potentiates the recruitment of NLG-1-stabilized-GABAARs, 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 GABAARs. Thus, our findings elucidate a mechanism for pre- and postsynaptic communication and inhibitory synaptic transmission and plasticity.

CaMKII mediates sexually dimorphic synaptic transmission at neuromuscular junctions in C. elegans

“…Endophilin is a membrane-associated protein that is required for SVs endocytosis ( Ringstad et al, 1999 ; Schmidt et al, 1999 ; Schuske et al, 2003 ). We used CRISPR/Cas9 system to insert a sequence encoding seven GFP11 fragments at the C-terminus of UNC-57/endophilin ( Hao et al, 2023 ). In parallel, the GFP1-10 fragment was constitutively expressed in DA and DB cholinergic motor neurons or GABAergic motor neurons under the control of the unc-129 or unc-25 promoters, respectively ( Fig.…”

“…S3, A and B ). Here, we focused our attention on UNC-43/CaMKII since it plays important roles in synaptic transmission and regulates the abundance of DCVs and SVs ( Hao et al, 2023 ; Hoover et al, 2014 ; Liu et al, 2007 ).…”

“…CaMKII is a serine/threonine-specific protein kinase activated by Ca 2+ /calmodulin and is required for synaptic transmission and plasticity at both pre- and postsynapses ( Hao et al, 2023 ; Lisman et al, 2002 ; Sheng and Hoogenraad, 2007 ). Previous studies have indicated that presynaptic CaMKII is required for the biogenesis of SVs and DCVs and for the synaptic transmission at Drosophila and C. elegans NMJs ( Carrillo et al, 2010 ; Hoover et al, 2014 ; Liu et al, 2007 ).…”

“…We examined the localization of endogenous UNC-43/CaMKII at cholinergic synapses by split GFP complementation system and observed a punctate pattern along the nerve cord ( Fig. 5, A and B ; Hao et al, 2023 ). We observed a dramatic increase in puncta fluorescence intensities in L4-staged and adult males compared with their respective hermaphrodites ( Fig.…”

Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization

“…Little is known about the role of presynaptic CaMKII in GABAergic synapse organization. A recent study has shown that, at Caenorhabditis elegans ( C. elegans ) neuromuscular junctions, presynaptic CaMKII (UNC-43, the C. elegans sole ortholog of CaMKII) trans-synaptically regulates postsynaptic GABA receptor recruitment by up-regulating presynaptic Nrxn surface delivery together with enhanced secretion of MADD-4B/Punctin ( Hao et al, 2023 ), which makes a protein complex with Nrxn1 and Nlgn1 ( Maro et al, 2015 ). Future studies with interneuron type-specific genetic manipulation of CaMKII and Src-mediated signaling pathways will be important to address how these pathways are linked with Nrxns in presynaptic terminals of each type of interneuron and define their GABAergic synapse specificity in developing mammalian brain circuits.…”