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Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition have not been investigated. Here, we report that USP6 is highly expressed in induced human neurons and that neuron-specific expression of USP6 enhances learning and memory in a transgenic mouse model. Similarly, USP6 expression regulates N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation and long-term depression in USP6 transgenic mouse hippocampi. Proteomic characterization of transgenic USP6 mouse cortex reveals attenuated NMDAR ubiquitination, with concomitant elevation in NMDAR expression, stability, and cell surface distribution with USP6 overexpression. USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. Together, these results indicate that USP6 enhances NMDAR stability to promote synaptic function and cognition. This study identifies the hominoid-specific USP6 as a novel deubiquitinase of NMDA receptors, and shows that neuronal expression of human USP6 transgene enhances cognitive and synaptic function in mice, suggesting a potential role of USP6 in the evolution of human intelligence. [ABSTRACT FROM AUTHOR]

Fungicides are frequently detected in the water bodies, however, the adverse effects of these fungicides on aquatic lives remain limited. To better understand the adverse effects of amisulbrom (AML) and isoflucypram (ISO) on embryogenesis, zebrafish embryos were exposed to two different fungicides, 0.75 μM amisulbrom (AML) and 2.5 μM isoflucypram (ISO), for 72 h. Transcriptome sequencing was employed to identify differentially expressed genes (DEGs) after AML and ISO exposure. A total of 571 and 3471 DEGs were detected between the libraries of the two fungicides-treated groups and the control, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that PPAR signaling pathway, phototransduction, ribosome and p53 signaling pathway were significantly enriched in response to both AML and ISO stress. Moreover, a number of DEGs involved in tyrosine metabolism, phagosome pathway, cell cycle pathway, extracellular matrix (ECM) receptor interaction pathway, and arginine and proline metabolism were specially enriched after exposure to AML; a number of DEGs involved in notch signaling pathway, drug metabolism, alanine, aspartate and glutamate metabolism, amino-acyl−tRNA biosynthesis, and protein processing in endoplasmic reticulum were significantly enriched after exposure to ISO. These results provide novel insights into the toxicological mechanisms underlying fish's responses to fungicides. [ABSTRACT FROM AUTHOR]