Summary: Researchers report that chemical modifications adding methyl groups to RNA can strengthen memory formation.
Source: UC Irvine.
Findings may lead to a better understanding of memory-related disorders.
Neurobiologists from the University of California, Irvine and the University of Queensland have uncovered new details about how experiences become stable long-term memories. Their work identifies a biochemical mechanism in the adult brain — the addition of methyl groups to RNA — that appears to support memory consolidation.
The research team, led by Timothy Bredy, associate professor of neurobiology & behavior at UCI, examined chemical modification of RNA called N6-methyladenosine (m6A). This modification can change how RNA behaves inside cells. The investigators found that increasing overall m6A levels in a specific brain region improved memory formation in mice. Their results were published June 22 in the Journal of Neuroscience.
To investigate m6A’s role in memory, the researchers profiled methylated RNA across the entire genome in brain tissue taken from mice shortly after they were trained on a learning task. They observed widespread, experience-dependent increases in m6A in the medial prefrontal cortex (mPFC) associated with new memory formation. The changes were concentrated near the stop codons of many mRNAs, including those linked to neuronal plasticity.
m6A is an epitranscriptomic mark — an RNA-level modification that can rapidly regulate gene expression without changing the underlying DNA code. Because epigenetic and epitranscriptomic mechanisms translate environmental signals into molecular responses, modulation of m6A provides a way for the brain to adapt gene activity during learning.
In cell culture experiments using primary cortical neurons, the team showed that the RNA demethylase FTO, an enzyme that removes m6A marks, altered the degradation profiles of transcripts that carried modulated m6A sites. In living animals, expression of both Fto and the m6A methyltransferase Mettl3 corresponded with the observed rise in m6A levels after training.
Importantly, when the researchers selectively reduced FTO levels in the medial prefrontal cortex, thereby increasing total m6A, mice displayed stronger consolidation of a learned fear response. “By genetically silencing an enzyme in a specific region of the brain involved in memory and adaptive behavior, we saw much better memory recall in mice,” said Jocelyn Widagdo, postdoctoral fellow and co-lead author of the study from the Queensland Brain Institute.
These findings indicate that dynamic regulation of m6A in the adult brain is an important epitranscriptomic mechanism associated with behavioral adaptation. Because m6A can fine-tune mRNA stability and expression rapidly, the process has potential relevance for conditions in which memory and gene regulation are impaired.
The study’s co-authors include Qiongyi Zhao, Marie-Jeanne Kempen, Men Chee Tan, Vikram Ratnu, Wei Wei, Laura Leighton, Paola Spadaro, Janette Edson and Victor Anggono, in addition to Jocelyn Widagdo and Timothy W. Bredy. The research was funded by the National Institutes of Mental Health (grant 1R01MH109588-01), the Australian National Health and Medical Research Council (APP1042051, APP1062570 and 477108), the Australian Research Council (DP1096148) and the John T. Reid Charitable Trust.
Source: Rahasson Ager — UC Irvine
Original research: “Experience-Dependent Accumulation of N6-Methyladenosine in the Prefrontal Cortex Is Associated with Memory Processes in Mice,” Journal of Neuroscience. Published online June 22, 2016. doi:10.1523/JNEUROSCI.4053-15.2016
Abstract
Experience-Dependent Accumulation of N6-Methyladenosine in the Prefrontal Cortex Is Associated with Memory Processes in Mice
The RNA modification N6-methyladenosine (m6A) influences mRNA stability and cell-type-specific developmental programming and is abundant in the adult brain. This study used transcriptome-wide profiling to show that m6A levels increase in the medial prefrontal cortex (mPFC) of mice in response to behavioral experience. Modulation of m6A was enriched near mRNA stop codons and affected genes involved in neuronal plasticity. In primary cortical neurons in vitro, altering m6A through the RNA demethylase FTO changed the degradation patterns of a subset of transcripts with modified sites. In vivo, expression of Fto and the m6A methyltransferase Mettl3 correlated with the rise in m6A after training. Targeted knockdown of FTO in the mPFC enhanced consolidation of cued fear memory. These findings indicate that dynamic regulation of m6A in the adult brain is an epitranscriptomic mechanism linked to behavioral adaptation.
SIGNIFICANCE STATEMENT N6-methyladenosine (m6A) is the most prevalent internal modification on RNA, yet its in vivo dynamics have been unclear. This work provides the first clear demonstration that m6A increases in the mouse medial prefrontal cortex following behavioral training. Reducing the m6A demethylase FTO in this brain region raises total m6A and strengthens memory consolidation. These results suggest that m6A is regulated by neuronal activity and may help fine-tune mRNA turnover during memory-related processes.