Synapse-Enriched m 6 A-Modified Malat1 Interacts with the Novel m 6 A Reader, DPYSL2, and Is Required for Fear-Extinction Memory

• Published in: The Journal of neuroscience Vol. 43; no. 43; pp. 7084 - 7100
• Main Authors: Madugalle, Sachithrani U, Liau, Wei-Siang, Zhao, Qiongyi, Li, Xiang, Gong, Hao, Marshall, Paul R, Periyakaruppiah, Ambika, Zajaczkowski, Esmi L, Leighton, Laura J, Ren, Haobin, Musgrove, Mason R B, Davies, Joshua W A, Kim, Gwangmin, Rauch, Simone, He, Chuan, Dickinson, Bryan C, Fulopova, Barbora, Fletcher, Lee N, Williams, Stephen R, Spitale, Robert C, Bredy, Timothy W
• Format: Journal Article
• Language: English
• Published: United States 25-10-2023
• Subjects: Animals; Extinction, Psychological; Fear - physiology; Learning - physiology; Male; Mice; RNA, Long Noncoding - metabolism; Synapses - metabolism; RNA m6A; long noncoding RNA; epitranscriptomic; memory; synapse; m6A reader
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0943-23.2023

The RNA modification N
-methyladenosine (m
A) regulates the interaction between RNA and various RNA binding proteins within the nucleus and other subcellular compartments and has recently been shown to be involved in experience-dependent plasticity, learning, and memory. Using m
A RNA-sequencing, we have discovered a distinct population of learning-related m
A- modified RNAs at the synapse, which includes the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (
). RNA immunoprecipitation and mass spectrometry revealed 12 new synapse-specific learning-induced m
A readers in the mPFC of male C57/BL6 mice, with m
A-modified
binding to a subset of these, including CYFIP2 and DPYSL2. In addition, a cell type- and synapse-specific, and state-dependent, reduction of m
A on
impairs fear-extinction memory; an effect that likely occurs through a disruption in the interaction between
and DPYSL2 and an associated decrease in dendritic spine formation. These findings highlight the critical role of m
A in regulating the functional state of RNA during the consolidation of fear-extinction memory, and expand the repertoire of experience-dependent m
A readers in the synaptic compartment.
We have discovered that learning-induced m
A-modified RNA (including the long noncoding RNA,
) accumulates in the synaptic compartment. We have identified several new m
A readers that are associated with fear extinction learning and demonstrate a causal relationship between m
A-modified
and the formation of fear-extinction memory. These findings highlight the role of m
A in regulating the functional state of an RNA during memory formation and expand the repertoire of experience-dependent m
A readers in the synaptic compartment.