Unraveling Neuronal Heterogeneity: Exploration of RNA Modifications in Synaptic Proteins

Researchers at The Picower Institute for Learning and Memory investigated neurons in Drosophila fruit flies to gain insights into neuronal communication diversity. Their research highlighted the crucial role of the protein complexin in managing neurotransmitter release. The team discovered that RNA alterations in complexin lead to various forms of the protein, impacting neuronal communication and synaptic growth. This information was originally reported by SciTechPost.com.

Neurons have been observed to produce up to eight distinct forms of a protein that influences neurotransmitter release, impacting their communication methods with other cells.

Neurons are natural communicators, interacting with other neurons, muscles, and cells by discharging neurotransmitters at synapses, leading to various functions from emotional to physical responses. However, even neurons of the same type exhibit differences in their communication styles. A recent study, published in Cell Reports and conducted by neurobiologists at The Picower Institute, sheds light on a molecular mechanism that may explain this varied neural interaction.

The study focused on muscle-controlling neurons in Drosophila fruit flies, which are common models in neuroscience due to their fundamental similarities to neurons in humans and other animals. These neurons communicate by releasing the neurotransmitter glutamate. Troy Littleton’s lab at MIT, specializing in neuronal communication regulation, noticed variations in neurotransmitter release patterns among individual neurons.

In their latest research on a protein that regulates neurotransmitter release, the scientists observed how RNA editing influenced the protein’s distribution and effectiveness. They found that different RNA edits of complexin resulted in varied distributions in motor neuron segments and differences in functionality. The study was conducted by Littleton’s team, including Elizabeth Brija, PhD.

Complexin’s Function in Neuronal Interaction

Over more than ten years, Littleton’s lab has demonstrated complexin’s role in limiting spontaneous glutamate communication. This protein controls the fusion of glutamate-filled vesicles at the synaptic membrane, conserving neurotransmitter for necessary functional purposes, like muscle stimulation. The lab identified two variants of complexin in flies (with mammals having four) and studied how the rarer 7B form, regulated by phosphorylation, differs in clamping effectiveness from the more common 7A form. The regulation of 7A was previously unclear, but it’s known that RNA transcribed for complexin formation is sometimes edited by an enzyme called ADAR.

Littleton’s team, led by Elizabeth Brija, PhD, examined whether RNA editing of complexin 7A influences glutamate release regulation. They found that RNA editing significantly affects the protein’s efficiency in preventing glutamate release, and this varies among neurons, which can produce up to eight different protein versions. While some edits were more prevalent, 96 percent of the 200 neurons studied showed some level of editing, affecting the protein’s C-terminus structure.

The team’s experiments demonstrated that different complexin 7A edits significantly impact electrical currents at synapses and synaptic growth with muscles. RNA editing might thus provide neurons with subtle communication control.

Littleton highlighted the nervous system’s ability to create varied neuronal behaviors by editing different RNA transcripts.

Broadening the Perspective: Other Protein Edits

The study also found that other key proteins in synaptic glutamate release, like synapsin and Syx1A, undergo different levels of RNA editing, suggesting tunability in synaptic communication.

The research, supported by The National Institutes of Health, The JPB Foundation, and The Picower Institute, involved meticulous RNA extraction and sequencing from 200 motor neurons, revealing three possible adenosine nucleotide swaps in the C-terminus, leading to eight protein versions. While the average neuron contained mostly unedited complexin 7A, the rest had varying frequencies of the seven edited forms.

Further functional tests revealed stark contrasts between the edited proteins. One common edit was less effective than the unedited version, while another was more effective, influencing glutamate release and synaptic growth. Combining unedited complexin with a weak-clamping edition in complexin-less flies led to a mix of effects, suggesting that each edition, and their combinations, can finely adjust glutamate release.

Reference: “Stochastic RNA editing of the Complexin C-terminus within single neurons regulates neurotransmitter release” by Elizabeth A. Brija, Zhuo Guan, Suresh K. Jetti, and J. Troy Littleton, 17 September 2023, Cell Reports. DOI: 10.1016/j.celrep.2023.113152

Co-authors include Zhuo Guan and Suresh Jetti, with support from The National Institutes of Health, The JPB Foundation, and The Picower Institute for Learning and Memory.

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• Implications of Synaptic Communication Research