A noncoding role of coding mRNA in monogenic olfactory receptor choice.

In a recent study, Pourmorady and colleagues uncovered a noncoding role for olfactory receptor (OR)-coding mRNA in mediating nuclear architecture and singular OR choice. The OR mRNAs reinforce the prevailing enhancer hub and inhibit other competitors, facilitating transition from polygenic to singular OR expression.

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

Sexually dimorphic behaviors are ubiquitous throughout the animal kingdom. Although both sex-specific and sex-shared neurons have been functionally implicated in these diverse behaviors, less is known about the roles of sex-shared neurons. Here, we discovered sexually dimorphic cholinergic synaptic transmission in C. elegans occurring at neuromuscular junctions (NMJs), with males exhibiting increased release frequencies, which result in sexually dimorphic locomotion behaviors. Scanning electron microscopy revealed that males have significantly more synaptic vesicles (SVs) at their cholinergic synapses than hermaphrodites. Analysis of previously published transcriptome identified the male-enriched transcripts and focused our attention on UNC-43/CaMKII. We ultimately show that differential accumulation of UNC-43 at cholinergic neurons controls axonal SV abundance and synaptic transmission. Finally, we demonstrate that sex reversal of all neurons in hermaphrodites generates male-like cholinergic transmission and locomotion behaviors. Thus, beyond demonstrating UNC-43/CaMKII as an essential mediator of sex-specific synaptic transmission, our study provides molecular and cellular insights into how sex-shared neurons can generate sexually dimorphic locomotion behaviors.

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

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.

CASK and FARP localize two classes of post-synaptic ACh receptors thereby promoting cholinergic transmission.

Changes in neurotransmitter receptor abundance at post-synaptic elements play a pivotal role in regulating synaptic strength. For this reason, there is significant interest in identifying and characterizing the scaffolds required for receptor localization at different synapses. Here we analyze the role of two C. elegans post-synaptic scaffolding proteins (LIN-2/CASK and FRM-3/FARP) at cholinergic neuromuscular junctions. Constitutive knockouts or muscle specific inactivation of lin-2 and frm-3 dramatically reduced spontaneous and evoked post-synaptic currents. These synaptic defects resulted from the decreased abundance of two classes of post-synaptic ionotropic acetylcholine receptors (ACR-16/CHRNA7 and levamisole-activated AChRs). LIN-2's AChR scaffolding function is mediated by its SH3 and PDZ domains, which interact with AChRs and FRM-3/FARP, respectively. Thus, our findings show that post-synaptic LIN-2/FRM-3 complexes promote cholinergic synaptic transmission by recruiting AChRs to post-synaptic elements.

Male pheromones modulate synaptic transmission at the C. elegans neuromuscular junction in a sexually dimorphic manner.

The development of functional synapses in the nervous system is important for animal physiology and behaviors, and its disturbance has been linked with many neurodevelopmental disorders. The synaptic transmission efficacy can be modulated by the environment to accommodate external changes, which is crucial for animal reproduction and survival. However, the underlying plasticity of synaptic transmission remains poorly understood. Here we show that in Caenorhabditis elegans, the male environment increases the hermaphrodite cholinergic transmission at the neuromuscular junction (NMJ), which alters hermaphrodites' locomotion velocity and mating efficiency. We identify that the male-specific pheromones mediate this synaptic transmission modulation effect in a developmental stage-dependent manner. Dissection of the sensory circuits reveals that the AWB chemosensory neurons sense those male pheromones and further transduce the information to NMJ using cGMP signaling. Exposure of hermaphrodites to the male pheromones specifically increases the accumulation of presynaptic CaV2 calcium channels and clustering of postsynaptic acetylcholine receptors at cholinergic synapses of NMJ, which potentiates cholinergic synaptic transmission. Thus, our study demonstrates a circuit mechanism for synaptic modulation and behavioral flexibility by sexual dimorphic pheromones.