RNA’s Pivotal Role in Fear Memory and PTSD Treatment

Summary: Researchers have revealed a groundbreaking role of RNA in fear-related learning and memory. Their study shows how noncoding RNA Gas5 influences neuronal excitability, impacting learning and memory processes.

Another study identified m6A-modified RNAs that regulate synaptic plasticity, crucial for fear extinction memory, a key factor in PTSD. These findings offer new insights into RNA’s role in the brain and potential RNA-based therapies for PTSD.

Key Facts:

  1. Noncoding RNA Gas5 coordinates RNA molecule trafficking in neurons, playing a critical role in learning and memory, especially fear extinction.
  2. Synapse-specific m6A-modified RNAs, identified in a separate study, are crucial for synaptic plasticity and fear extinction memory, impacting PTSD treatment.
  3. This research provides a deeper understanding of RNA in brain function and opens new avenues for RNA therapeutic approaches for PTSD and phobias.

Source: University of Queensland

Researchers from The University of Queensland have discovered a new way ribonucleic acid (RNA) impacts fear-related learning and memory.

Professor Timothy Bredy from UQ’s Queensland Brain Institute said this is an exciting example of RNA’s role in fine-tuning the cellular functions in the brain.

In a paper published in Nature Communications, researchers demonstrated that a noncoding RNA known as Gas5 coordinates the trafficking and clustering of RNA molecules inside the long processes of neurons, and orchestrating neuronal excitability in real time that contributes to learning and memory.  

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This new information may inform the development of future RNA therapies to address PTSD. Credit: Neuroscience News

“Understanding the complex world of RNA is a rapidly emerging area of neuroscience research, where we are constantly learning more about how different classes of RNA control the communication between and within brain cells,” Professor Bredy said. 

“In this study, we found learning-related RNAs at the synapse and one, in particular, called Gas5 seems to be uniquely required for fear extinction memory. 

“There’s a lot more happening with these kinds of RNA molecules than we first thought and that fact they influence cellular function on a millisecond timeframe, which mirrors the real time changes in synaptic function that happen in the brain during learning, is extraordinary.

Non-coding RNA may be the missing link to understanding how the brain processes critically important inputs that lead to the formation of memory”

This study builds on earlier findings this year from the Bredy Lab which identified a separate population of learning-related RNAs that accumulate near the synapse – the junction between neurons that allow them to communicate.

In that paper, published in the Journal of Neuroscience, they uncovered several new synapse-specific RNA that harbour a specific chemical tag called N6-methyladenosine (m6A).

Lead author Dr Sachithrani Madugalle said the findings highlighted the importance of m6A-modified RNAs in regulating synaptic plasticity.

“Readers are proteins that bind to the chemical tag and direct it to locations and functions,” Dr Madugalle said.

“The readers allowed us to determine the functional role of m6A-modified RNA molecules in the formation of new memories.

“By examining one such RNA, Malat1, we discovered the key proteins that interact with this RNA and support processes related to an important type of memory called fear extinction.

“Fear extinction impairment is associated with post-traumatic stress disorder (PTSD).

“When Malat1 is chemically decorated with m6A, this allows it to interact with different proteins in the synaptic compartment, which can then alter the mechanisms involved in the formation of fear extinction memory.

“This new information may inform the development of future RNA therapies to address PTSD.

“By understanding where, when, and how an RNA molecule is activated and having a precise marker will help us identify the target for therapies.”

In addition, in both studies the team employed an innovative new tool that allowed them to manipulate the functional state of an RNA molecule, together with Professor Bryan Dickinson and Dr. Simone Rauch at the University of Chicago.

“We are now looking for ways to harness RNA to control the aspects of synaptic function underlying memory formation and to potentially develop an RNA therapeutic for the treatment of PTSD and phobia,” Professor Bredy said.

About this genetics, memory, and PTSD research news

Author: Lisa Clarke
Source: University of Queensland
Contact: Lisa Clarke – University of Queensland
Image: The image is credited to Neuroscience News

Original Research: Open access.
Fear extinction is regulated by the activity of long noncoding RNAs at the synapse” by Sachithrani Madugalle et al. Nature Communications

Closed access.
Synapse-Enriched m6A-Modified Malat1 Interacts with the Novel m6A Reader, DPYSL2, and Is Required for Fear-Extinction Memory” by Sachithrani Madugalle et al. Journal of Neuroscience


Fear extinction is regulated by the activity of long noncoding RNAs at the synapse

Long noncoding RNAs (lncRNAs) represent a multidimensional class of regulatory molecules that are involved in many aspects of brain function.

Emerging evidence indicates that lncRNAs are localized to the synapse; however, a direct role for their activity in this subcellular compartment in memory formation has yet to be demonstrated.

Using lncRNA capture-seq, we identified a specific set of lncRNAs that accumulate in the synaptic compartment within the infralimbic prefrontal cortex of adult male C57/Bl6 mice.

Among these was a splice variant related to the stress-associated lncRNA, Gas5. RNA immunoprecipitation followed by mass spectrometry and single-molecule imaging revealed that this Gas5 isoform, in association with the RNA binding proteins G3BP2 and CAPRIN1, regulates the activity-dependent trafficking and clustering of RNA granules.

In addition, we found that cell-type-specific, activity-dependent, and synapse-specific knockdown of the Gas5 variant led to impaired fear extinction memory.

These findings identify a new mechanism of fear extinction that involves the dynamic interaction between local lncRNA activity and RNA condensates in the synaptic compartment.


Synapse-Enriched m6A-Modified Malat1 Interacts with the Novel m6A Reader, DPYSL2, and Is Required for Fear-Extinction Memory

The RNA modification N6-methyladenosine (m6A) 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 m6A RNA-sequencing, we have discovered a distinct population of learning-related m6A- modified RNAs at the synapse, which includes the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (Malat1). RNA immunoprecipitation and mass spectrometry revealed 12 new synapse-specific learning-induced m6A readers in the mPFC of male C57/BL6 mice, with m6A-modified Malat1 binding to a subset of these, including CYFIP2 and DPYSL2.

In addition, a cell type- and synapse-specific, and state-dependent, reduction of m6A on Malat1 impairs fear-extinction memory; an effect that likely occurs through a disruption in the interaction between Malat1 and DPYSL2 and an associated decrease in dendritic spine formation.

These findings highlight the critical role of m6A in regulating the functional state of RNA during the consolidation of fear-extinction memory, and expand the repertoire of experience-dependent m6A readers in the synaptic compartment.

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