The interaction of Synapsin 2a and Synaptogyrin-3 regulates fear extinction in mice.

The mechanisms behind a lack of efficient fear extinction in some individuals are unclear. Here, by employing a principal components analysis-based approach, we differentiated the mice into extinction-resistant and susceptible groups. We determined that elevated synapsin 2a (Syn2a) in the infralimbic cortex (IL) to basolateral amygdala (BLA) circuit disrupted presynaptic orchestration, leading to an excitatory/inhibitory imbalance in the BLA region and causing extinction resistance. Overexpression or silencing of Syn2a levels in IL neurons replicated or alleviated behavioral, electrophysiological, and biochemical phenotypes in resistant mice. We further identified that the proline-rich domain H in the C-terminus of Syn2a was indispensable for the interaction with synaptogyrin-3 (Syngr3) and demonstrated that disrupting this interaction restored extinction impairments. Molecular docking revealed that ritonavir, an FDA-approved HIV drug, could disrupt Syn2a-Syngr3 binding and rescue fear extinction behavior in Syn2a-elevated mice. In summary, the aberrant elevation of Syn2a expression and its interaction with Syngr3 at the presynaptic site were crucial in fear extinction resistance, suggesting a potential therapeutic avenue for related disorders.

[Advances in the roles and mechanisms of nonsense-mediated mRNA decay in embryonic development].

Nonsense-mediated mRNA decay (NMD) is originally identified as a widespread mRNA surveillance machinery in degrading 'aberrant' mRNA species with premature termination codons (PTCs) rapidly, which protects the cells from the accumulation of truncated proteins. Recent studies show that NMD can also regulate the degradation of normal gene transcripts, which execute important cellular and physiological functions. Therefore, NMD is considered as a highly conserved post-transcriptional regulatory mechanism in eukaryotes. NMD modulates 3% to 20% of the transcriptome from yeast to human directly or indirectly, which is essential for various physiological processes, such as cell homeostasis, stress response, proliferation, and differentiation. NMD can regulate the level of transcripts that involves in development, and single knockout of most NMD factors has an embryonic lethal effect. NMD plays an important role in the self-renewal, differentiation of embryonic stem cells and is critical during embryonic development. In this review, we summarized the latest advances in the roles and mechanisms of NMD in embryonic development, in order to provide new ideas for the research on embryonic development and the treatment of embryonic development related diseases.

Safety evaluation of chinese medicine injections with a cell imaging-based multiparametric assay revealed a critical involvement of mitochondrial function in hepatotoxicity.

The safety of herbal medicine products has been a widespread concern due to their complex chemical nature and lack of proper evaluation methods. We have adapted a sensitive and reproducible multiparametric cell-based high-content analysis assay to evaluate the hepatic-safety of four Chinese medicine injections and validated it with classical animal-based toxicity assays. Our results suggested that the reported hepatotoxicity by one of the drugs, Fufangkushen injection, could be attributed at least in part to the interference of mitochondrial function in human HepG2 cells by some of its constituents. This method should be useful for both preclinical screen in a drug discovery program and postclinical evaluation of herbal medicine preparations.