Abstract
Long-term potentiation (LTP) of synaptic transmission is recognized as a cellular mechanism for learning and memory storage. Although de novo gene transcription is known to be required in the formation of stable LTP, the molecular mechanisms underlying synaptic plasticity remain elusive. Noncoding RNAs have emerged as major regulatory molecules that are abundantly and specifically expressed in the mammalian brain. By combining RNA-seq analysis with LTP induction in the dentate gyrus of live rats, we provide the first global transcriptomic analysis of synaptic plasticity in the adult brain. Expression profiles of mRNAs and long noncoding RNAs (lncRNAs) were obtained at 30 min, 2 and 5 h after high-frequency stimulation of the perforant pathway. The temporal analysis revealed dynamic expression profiles of lncRNAs with many positively, and highly, correlated to protein-coding genes with known roles in synaptic plasticity, suggesting their possible involvement in LTP. In light of observations suggesting a role for retrotransposons in brain function, we examined the expression of various classes of repeat elements. Our analysis identifies dynamic regulation of LINE1 and SINE retrotransposons, and extensive regulation of tRNA. These experiments reveal a hitherto unknown complexity of gene expression in long-term synaptic plasticity involving the dynamic regulation of lncRNAs and repeat elements. These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity in both the healthy brain and in neurodegenerative and neuropsychiatric disorders.
Highlights
Long-lasting changes in synaptic communication are thought to underlie memory storage and adaptive functions of the brain related to fear, anxiety and reward (Malenka and Bear, 2004; Whitlock, 2006; Nabavi et al, 2014; Baudry et al, 2015)
NMDA Receptor-dependent Long-term potentiation (LTP)-induction in Rat Dentate Gyrus in vivo: Validation of Arc Expression by Transcriptomic Analysis LTP was induced in the dentate gyrus (DG) of urethaneanesthetized rats using a well-characterized paradigm of patterned, high-frequency stimulation (HFS) of the medial perforant path input to DG granule cells (Figure 1A) (Messaoudi et al, 2002; Panja et al, 2009)
The increase in Arc expression was abolished in CPP-treated animals and was absent in the baseline test stimulus (BTS) control group, and only a slight increase (2-fold-change, p < 0.05) in Arc expression was observed in the neighboring cornu amonis (CA) region of the hippocampus compared to 30 min, 2 h, and 5 h (86 ± 19, 140 ± 37, 144 ± 19, mean fold-change ± s.e.m, respectively), post-HFS
Summary
Long-lasting changes in synaptic communication are thought to underlie memory storage and adaptive functions of the brain related to fear, anxiety and reward (Malenka and Bear, 2004; Whitlock, 2006; Nabavi et al, 2014; Baudry et al, 2015). Noncoding RNAs in synaptic plasticity frequently addressed, the complex molecular network underlying long-lasting synaptic changes is not well understood. One particular aspect of synaptic plasticity that has seldom been explored is the role of noncoding regions of the genome and the potential regulatory functions that they contain. The argument that these noncoding regions may be important in brain function arises predominantly from the observation that organisms with increasingly complex brains have genomes comprising increasingly large proportions of noncoding DNA. One means through which noncoding DNA transacts function is through expression into regulatory RNAs, which have been speculated upon previously to function in long-term memory formation (Mercer et al, 2007). The function of the vast majority of these transcripts is unknown and remains an area of some controversy (Clark et al, 2011)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
