eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior.

Regulation of mRNA translation is essential for brain development and function. Translation elongation factor eEF2 acts as a molecular hub orchestrating various synaptic signals to protein synthesis control and participates in hippocampus-dependent cognitive functions. However, whether eEF2 regulates other behaviors in different brain regions has been unknown. Here, we construct a line of Eef2 heterozygous (HET) mice, which show a reduction in eEF2 and protein synthesis mainly in excitatory neurons of the prefrontal cortex. The mice also show lower spine density, reduced excitability, and AMPAR-mediated synaptic transmission in pyramidal neurons of the medial prefrontal cortex (mPFC). While HET mice exhibit normal learning and memory, they show defective social behavior and elevated anxiety. Knockdown of Eef2 in excitatory neurons of the mPFC specifically is sufficient to impair social novelty preference. Either chemogenetic activation of excitatory neurons in the mPFC or mPFC local infusion of the AMPAR potentiator PF-4778574 corrects the social novelty deficit of HET mice. Collectively, we identify a novel role for eEF2 in promoting prefrontal AMPAR-mediated synaptic transmission underlying social novelty behavior.

Discovery of Neuritogenic Securinega Alkaloids from Flueggea suffruticosa by a Building Blocks-Based Molecular Network Strategy.

A combined strategy of building blocks recognition and molecular network construction, termed the building blocks-based molecular network (BBMN), was first presented to facilitate the efficient discovery of novel natural products. By mapping the BBMN of the total alkaloid fraction of Flueggea suffruticosa, three Securinega alkaloids (SEAs) with unusual chemical architectures, suffranidines A-C (1-3), were discovered and isolated. Compound 1 characterizes an unprecedented 8/5/6/5/6/6/6/6-fused octacyclic scaffold with a unique cage-shaped 3-azatricyclo[6.4.0.03,11 ]dodecane core. Compounds 2 and 3 are highly modified SEA dimers that incorporate additional C6 motifs. A hypothetical biosynthetic pathway for 1-3 was proposed. In addition, 1 significantly induced neuronal differentiation and neurite extension by upregulating eukaryotic elongation factor 2 (eEF2)-mediated protein synthesis.

Dimeric Diarylheptanoids with Neuroprotective Activities from Rhizomes of Alpinia officinarum.

Two novel dimeric diarylheptanoids, alpinidinoids A [(±)-1] and B (2), with two unusual coupling patterns, together with a new naturally occurring diarylheptanoid dimer possessing a rare pyridine ring linkage (alpinidinoid C, 3), were isolated from the rhizomes of Alpinia officinarum. Their structures including absolute configurations were determined by extensive spectroscopic methods and theoretical calculations. All isolates were examined for their neuroprotective activities against oxygen-glucose deprivation and reoxygenation (OGD/R) damage in primary cortical neurons. Remarkably, the dextrorotatory enantiomer of alpinidinoid A [(+)-1] significantly ameliorated OGD/R-induced neuronal apoptosis, which was dependent on the activation of the AKT/mTOR signaling pathway.

Flueggeacosines A-C, Dimeric Securinine-Type Alkaloid Analogues with Neuronal Differentiation Activity from Flueggea suffruticosa.

Flueggeacosines A-C (1-3), three dimeric securinine-type alkaloid analogues with unprecedented skeletons, were isolated from Flueggea suffruticosa. Compounds 1 and 2 are the first examples of C-3-C-15' connected dimeric securinine-type alkaloids. Compound 3 is an unprecedented heterodimer of securinine-type and benzoquinolizidine alkaloids. Biosynthetic pathways for 1-3 were proposed on the basis of the coexisting alkaloid monomers as the precursors. Compound 2 exhibited significant activity in promoting neuronal differentiation of Neuro-2a cells.