miR-181a Participates in Contextual Fear Memory Formation Via Activating mTOR Signaling Pathway.

Long-term memory formation has been proven to require gene expression and new protein synthesis. MicroRNAs (miRNAs), as an endogenous small non-coding RNAs, inhibit the expression of their mRNA targets, through which involve in new memory formation. In this study, elevated miR-181a levels were found to be responsible for hippocampal contextual fear memory consolidation. Using a luciferase reporter assay, we indicated that miR-181a targets 2 upstream molecules of mTOR pathway, namely, PRKAA1 and REDD1. Upregulated miR-181a can downregulate the PRKAA1 and REDD1 protein levels and promote mTOR activity to facilitate hippocampal fear memory consolidation. These results indicate that miR-181a is involved in hippocampal contextual fear memory by activating the mTOR signaling pathway. This work provides a novel evidence for the role of miRNAs in memory formation and demonstrates the implication of mTOR signaling pathway in miRNA processing in the adult brain.

Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB.

Multiple studies have established that brain-derived neurotrophic factor (BDNF) plays a critical role in the regulation of synaptic plasticity via its receptor, TrkB. In addition to being phosphorylated, TrkB has also been demonstrated to be ubiquitinated. However, the mechanisms of TrkB ubiquitination and its biological functions remain poorly understood. In this study, we demonstrate that ubiquitin C-terminal hydrolase L1 (UCH-L1) promotes contextual fear conditioning learning and memory via the regulation of ubiquitination of TrkB. We provide evidence that UCH-L1 can deubiquitinate TrkB directly. K460 in the juxtamembane domain of TrkB is the primary ubiquitination site and is regulated by UCH-L1. By using a peptide that competitively inhibits the association between UCH-L1 and TrkB, we show that the blockade of UCH-L1-regulated TrkB deubiquitination leads to increased BDNF-induced TrkB internalization and consequently directs the internalized TrkB to the degradation pathway, resulting in increased degradation of surface TrkB and attenuation of TrkB activation and its downstream signaling pathways. Moreover, injection of the peptide into the DG region of mice impairs hippocampus-dependent memory. Together, our results suggest that the ubiquitination of TrkB is a mechanism that controls its downstream signaling pathways via the regulation of its endocytosis and postendocytic trafficking and that UCH-L1 mediates the deubiquitination of TrkB and could be a potential target for the modulation of hippocampus-dependent memory.SIGNIFICANCE STATEMENT Ubiquitin C-terminal hydrolase L1 (UCH-L1) has been demonstrated to play important roles in the regulation of synaptic plasticity and learning and memory. TrkB, the receptor for brain-derived neurotrophic factor, has also been shown to be a potent regulator of synaptic plasticity. In this study, we demonstrate that UCH-L1 functions as a deubiquitinase for TrkB. The blockage of UCH-L1-regulated deubiquitination of TrkB eventually results in the increased degradation of surface TrkB and decreased activation of TrkB and its downstream signaling pathways. In vivo, UCH-L1-regulated TrkB deubiquitination is necessary for hippocampus-dependent memory. Overall, our study provides novel insights into the mechanisms of UCH-L1-mediated neurobiological functions and suggests that ubiquitination is an important regulatory signal for TrkB functions.