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A novel memory preservation mechanism by epigenetic regulation

Neurons and their synapses in the brain are plastic. The synaptic weights and the neuronal excitability are adjustable to incorporate new information and change the responses of the neural network. The stimuli-induced neural activities rewire the neural circuits in an activity-dependent manner, leaving memory traces in the brain. One intriguing question is if the activities induced by the external stimuli keep on changing the brain circuit, how could the memory be preserved. This question is called "plasticity-stability dilemma". According to a recent research by Dr. Guan's group in Tsinghua University, a memory preservation mechanism in memory trace neurons is triggered by the neuronal activation to reduce the neuronal plasticity and to protect memories from disruption. On March 27th, 2017, the website of Nature Neuroscience online published the research article, entitled “Activity-induced histone modifications govern Neurexin-1 splicing and memory preservation”.  JiSong Guan’s group discovered that memory related neurons undergo epigenetic modifications on specific genomic loci after learning via AMPK pathway. These cellular processes further determine the alternative splicing isoform of synaptic adhesion molecule so that the plasticity and the connectivity of memory related neurons are suppressed. Such activity-dependent epigenetic modifications contribute to the memory stability.


The memory preservation mechanism in the brain

Memories are stored in the brain by the activity-induced modifications in specific synapses to hold the information. Paradoxically, neuronal activity does not change the circuits of consolidated memories. The neuronal mechanism underlying this phenomenon is unclear. Previous studies show that Epigenetic mechanisms are involved in the formation, consolidation and reconsolidation of memories. Recent discoveries suggest that histone modification might repress the plasticity in circuit of remote memory, underlying the robustness of traumatic memories. However, it was still unknown what has happened in the memory-related neurons after learning. In this recent study, Xinlu Ding and her colleagues directly analyzed the molecular composition in the memory related neurons by sorting out of the hippocampal memory trace neurons via FACS of the EGR1-EGFP mouse. They found that learning induces long-lasting epigenetic modifications in the memory related neurons, which regulate the alternative splicing of specific gene loci, especially the alternative splicing site 4 of Nrxn1 gene, and therefore suppress the synapse connections and preserve the memory.

The learning induced epigenetic regulation in the memory related neuron in the mouse DG area underlies memory preservation.

Xinlu Ding and her colleagues further identified the whole signaling pathway mediating the neural activity-induced histone modificaitons on the alternative splicing site 4 of Nrxn1 gene. Specifically, they found high frequency firing of memory trace neurons activates the AMPK, which phosphorylates p66α, a DNA binding protein recognizing the Nrxn1 splicing site 4(SS4). Phosphorylated p66α further recruits epigenetic regulator HDAC2, which further enriches Suv39h1 to establish the repressive histone modifications around the Nrxn1 SS4 region. Accumulation of repressive epigenetic markers significantly reduces the elongation rate of RNA polymerase II around the SS4 site and increases the inclusion of the alternatively spliced exon in the transcription-coupled splicing process. Removal of Suv39h1 abolished the activity-dependent switch of neurexin-1 splice isoform choice and reduced the stability of established memories.

This study implicates a cellular and molecular mechanism underlying memory preservation and provides a novel and promising avenue to the treatment of various neurology disorders, including PTSD and Alzheimer’s disease. Importantly, Ding's work revealed a novel regulation of plasticity in 24 hours after the stimuli. This discovery largely extends the knowledge of synaptic plasticity beyond the well-established short-term regulation. This newly identified plasticity rules will inspire the neuro-morphic computing to generate novel learning algorithms, especially to create the neural networks that could hold long-term memory to improve incremental learning.

Prof. JiSong Guan is the corresponding author. Xinlu Ding (PhD students from the Peking University-Tsinghua University-NIBS (PTN) Joint Graduate Program) and Sanxiong Liu (PhD student from Center for Life Sciences) are the co-first authors of this paper. Prof. Wei Xie, Prof. Jiawei Wu and Prof. Yichang Jia from Tsinghua University contributed to this work. The work is supported by grants from the National Basic Research Program of China, NSFC and funding support from Brain Inspired Computing Research, Tsinghua University, Beijing Municipal Science & Technology Commission and Beijing NOVA program.

Related publication:

Xinlu Ding, SanXiong Liu, Miaomiao Tian, Wenhao Zhang, Tao Zhu, Dongdong Li,

Jiawei Wu, HaiTeng Deng, Yichang Jia, Wei Xie, Hong Xie & Ji-Song Guan*(2017) Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation. Nat Neurosci. doi:10.1038/nn.4536

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