Neuronal activity modulates synapse formation in the developing PDE axon. a, Schematic representation and line scan of the PDE axon and its synapses labeled using a combinatorial approach. The endogenous FLP-on (FRT) GFP::ELKS-1 labels active zones and the endogenous FLP-on (FRT3) mScarlet::TBA-1 labels microtubules (for axon morphology) when combined with a transgene expressing a specific dopaminergic flippase (dat-1p::FLP). b, Top: Schematic representation of PDE silencing experiments. Transgenic animals expressing dat-1p::HisCl1 were placed on histamine-containing medium at the L2 stage and imaged at the L4 stage. Bottom: Schematic representation of PDE excitation experiments. Transgenic animals expressing dat-1p::ChR2 were subjected to blue light at the L2 or L4 stage and imaged 2 h or 48 h after treatment. This diagram was created with BioRender.com. c, Line scans of ELKS-1 in the PDE axon of wyEx8629(dat-1p::HisCl) animals treated with 0 mM or 10 mM histamine. d, Quantification of ELKS-1 in the PDE of animals shown in c (n = 14 for both conditions). e, Line scans of ELKS-1 in the PDE axon of wyEx10629(dat-1p::ChR2) animals treated with or without blue light. f, Quantification of ELKS-1 of animals shown in e (n = 19 for both conditions). Credit: Neuroscience of Nature (2024). DOI: 10.1038/s41593-024-01728-x
Synapses are junctions through which neurons communicate with each other or with other types of cells. Synapses form throughout a person’s life, but their strength and number change over time, a phenomenon known as synaptic plasticity.
While neuroscience studies have already provided much information on the composition and function of synapses, the genetic mechanisms that orchestrate their formation remain poorly understood. Experimental results suggest that neuronal activity plays a key role in synapse formation, but the interaction between this activity and genetic mechanisms remains largely unexplored.
Researchers from Stanford University, Stony Brook University and other institutes in the United States recently conducted a study aimed at filling this gap in the literature, by examining dopaminergic neurons in the multicellular organism Caenorhabditis elegans. Their paper, published in Neuroscience of Natureunveils a robust genetic program that could underlie synapse formation via neuronal activity.
“Although the molecular composition and architecture of synapses have been extensively studied, much less is known about the genetic programs that directly activate synaptic gene expression and how they are modulated,” Callista Yee, Yutong Xiao, and colleagues wrote in their paper. “Using Caenorhabditis elegans dopaminergic neurons, we reveal that EGL-43/MECOM and FOS-1/FOS control an activity-dependent program of synaptogenesis.”
Yee, Xiao and their colleagues have proposed that synaptic genes are controlled by two different mechanisms. One involves programs that regulate gene expression patterns during development, while the other depends on neuronal activity.
Their recent study aimed to better understand how these two different mechanisms converge to promote synapse formation during development. To do so, they conducted experiments on Caenorhabditis elegans, a small roundworm often used as a model organism in biological research.
The researchers modulated the activity of dopaminergic neurons in this organism using optogenetic and chemogenetic techniques, and then observed how this impacted the expression of presynaptic proteins. The results they collected suggest that neuronal activity plays a key role in synapse formation.
The team then sought to identify the genetic programs regulated by neuronal activity that promote synapse formation. This led them to discover two genes/proteins that control an activity-regulated process by which new synapses are formed, namely EGL-43/MECOM and FOS-1/FOS.
“Loss of either factor dramatically reduces presynaptic protein expression,” the researchers wrote. “Both factors bind directly to synaptic gene promoters and act in concert with CUT homeobox transcription factors to activate transcription. egl-43 and fos-1 mutually promote each other’s expression, and increased binding affinity of FOS-1 to the egl-43 locus results in increased presynaptic protein expression and synaptic function. EGL-43 regulates the expression of multiple transcription factors, including activity-regulated factors and developmental factors that define multiple aspects of dopaminergic identity.”
The recent work of this research team demonstrates a mechanism by which neuronal activity modulates the genetic programs that control synapse formation in Caenorhabditis elegans. While this mechanism has so far only been observed in dopaminergic neurons, the team believes that similar mechanisms also exist in different types of neurons.
In their next studies, they plan to study how the genetic program they discovered is regulated over time. They may also explore how this program interacts with other molecular processes to support synaptic gene expression.
More information:
Callista Yee et al, An activity-regulated transcriptional program directly drives synaptogenesis, Neuroscience of Nature (2024). DOI: 10.1038/s41593-024-01728-x
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