Summary: Researchers at the University of Nottingham report that reversible chemical changes to RNA at synapses—specifically removal of methyl groups—may act as a synaptic tag. This process influences how neurons communicate and could play a role in reversible psychiatric conditions like anxiety and in early stages of neurodegenerative diseases such as dementia.
Source: University of Nottingham
Scientists from the University of Nottingham have shown that reversing chemical marks on RNA at neural synapses —a process driven by the demethylase ALKBH5—may serve as a local synaptic tag and contribute to synaptic dysfunction in reversible psychiatric conditions and early neurodegeneration.
Published in Molecular Psychiatry, this study advances our understanding of synaptic plasticity and RNA epitranscriptomic regulation. The findings point to new molecular targets for disorders of memory and mental health by linking RNA methylation dynamics to synaptic activity and protein handling.
The work was led by Dr Helen Miranda Knight in the School of Life Sciences, with collaborators across the Schools of Medicine, Life Sciences and Bioscience at the University of Nottingham.
Investigations used the university’s Deep seq, SLIM microscopy and Nanoscale and Microscale Research Centre facilities to track RNA modifications at nanoscale resolution and to profile the methylated RNA landscape in human brain tissue.
Neurons communicate at synapses by releasing molecular signals that trigger responses in neighbouring cells. When we learn or form memories, specific synaptic connections are strengthened through local protein synthesis and reorganisation. Loss or malfunction of these synaptic circuits underlies impairments in cognition and behaviour seen in dementia and some mental health disorders.
Proteins required for synaptic function are produced from messenger RNAs (mRNAs). For precise synaptic responses, certain mRNAs must be available at the right synapse at the right moment. One proposed mechanism is “synaptic tagging,” where local molecular signals mark active synapses and direct RNA and protein resources to those sites.
A key epitranscriptomic mark is N6-methyladenosine (m6A), where a methyl group is added to adenine bases in RNA. This modification alters how proteins recognise and bind RNAs, often modulating translation or stability. The new study demonstrates that m6A marks are not static: they can be removed at active synapses by the demethylase ALKBH5, suggesting a dynamic mechanism for local regulation of mRNA function.
Using advanced imaging, the team visualised changes in m6A-modified RNAs at activated synapses over time and space. Parallel m6A-sequencing of human hippocampal and parahippocampal tissue characterised distinct methylation profiles in grey and white matter, highlighting that m6A patterns depend strongly on cellular context and brain region.
The researchers observed coordinated behaviour of m6A-binding “reader” proteins, including YTHDF1 and YTHDF3, and the “eraser” ALKBH5 in response to synaptic activation. At early stages of synaptic plasticity, both readers and the eraser co-localised with modified RNAs at activated glutamatergic postsynaptic sites; at later stages the readers predominated. These dynamics suggest temporally distinct roles for m6A effectors during synaptic maturation and plasticity.
Importantly, the study found evidence that m6A effector proteins themselves are subject to epitranscriptional and post-translational regulation, implying multilayered control of synaptic protein cascades. The authors propose that regulated availability of m6A machinery, together with RNA modification status, could facilitate assembly of condensed nanodomains at synapses—possibly via liquid-liquid phase separation—thereby contributing to localised translation and synaptic tagging.
Dr Knight commented: “These results reveal a genomic mechanism that controls synaptic communication: methyl groups are added to RNA messages and then removed at active synapses. This reversible RNA demethylation by ALKBH5 appears to be intrinsic to synaptic tagging, with implications for normal cognitive processes as well as for reversible psychiatric disorders such as anxiety or addiction and for early-stage neurodegenerative conditions like dementia.”
About this neuroscience research news
Author: Press Office
Source: University of Nottingham
Contact: Press Office – University of Nottingham
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Original Research: Open access.
“Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging” by Braulio Martinez De La Cruz, Robert Markus, Sunir Malla, Maria Isabel Haig, Chris Gell, Fei Sang, Eleanor Bellows, Mahmoud Awad Sherif, Denise McLean, Anbarasu Lourdusamy, Tim Self, Zsuzsanna Bodi, Stuart Smith, Michael Fay, Ian A. Macdonald, Rupert Fray, Helen Miranda Knight. Molecular Psychiatry
Abstract
Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging
Synaptic plasticity—the cellular basis of learning and memory—depends on local translation of mRNAs at activated synapses. The synaptic tagging hypothesis offers an explanation for how specific mRNAs become locally available at activated synapses, but the molecular identity and regulation of those tags remain incompletely understood. N6-methyladenosine (m6A) modification of RNA influences mRNA fate, including translation and stability.
Using advanced microscopy, we show that demethylation of m6A by the eraser protein ALKBH5 occurs at active synaptic ribosomes and is associated with short-term synaptic plasticity. At activated glutamatergic postsynaptic sites, both the reader proteins YTHDF1 and YTHDF3 and the eraser ALKBH5 increase their co-localisation with m6A-modified RNAs during early plasticity; in late-stage plasticity the readers remain highly associated with modified RNAs while ALKBH5 association decreases.
Differential roles for YTHDF1 and YTHDF3 are evident during synaptic maturation, suggesting that temporal and subcellular distribution of these effectors determines specific functions. m6A-sequencing of human parahippocampal tissue reveals distinct methylome profiles in white and grey matter, underscoring that cellular context dictates regulated pathways. Furthermore, m6A effector proteins themselves undergo epitranscriptional and post-translational modification, indicating co-regulation of protein cascades by m6A processes.
We propose that the availability of m6A effector machinery, combined with dynamic RNA modification, contributes to the formation of condensed synaptic nanodomains—potentially via liquid-liquid phase separation—and supports localised translation as part of synaptic tagging. Our data support ALKBH5-mediated m6A demethylation as an intrinsic element of synaptic tagging and identify it as a molecular switch that can alter the RNA methylome, influence synaptic function, and contribute to potentially reversible disease states.