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SummaryADAMs (a disintegrinandmetalloproteinase) are transmembrane proteins with cell adhesion and protease activities that contain disintegrin and metalloproteinase domains. ADAM10, a member of the ADAM family, is widely expressed in the brain. There are >40 substrates reported for ADAM10, including Notch, Delta-like ligand-1 (Dll1), and N-cadherin. To date, however, its function in the brain has been largely unknown. We used genetic manipulation to deleteAdam10specifically from glial progenitors in developing brains and observed that conditional knockout mice showed locomotor abnormalities. They all died within 4 months with apparent defects in the cerebellum. By comprehensively analyzing data from bulk RNA sequencing, single-cell RNA sequencing, and staining of the cerebellum, we found that ADAM10 promoted astrocyte generation under physiological conditions. Upon the removal ofAdam10in glial progenitors, the production of oligodendrocytes vastly increased, whereas the generation of astrocytes was substantially inhibited. Our results showed that ADAM10 plays a critical role in macroglial cell fate decisions during brain development.

Neuroinflammation plays an important role in brain damage after acute carbon monoxide poisoning (ACOP). The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing (NLRP) 3 inflammasome triggers the activation of inflammatory caspases and maturation of interleukin (IL)-1β and -18, and has been linked to various human autoinflammatory and autoimmune diseases. In this study we investigated the effects of hyperbaric oxygen (HBO2) on NLRP3 inflammasome activation after ACOP. Mice were randomly divided into four groups: sham group (exposure to normobaric air – i.e., 21% O2 at 1 atmosphere absolute); HBO2-only group; CO + normobaric air group; and CO + HBO2 group. Cognitive function was evaluated with the Morris water maze; myelin injury was assessed by Fluoro-Myelin GreenTM fluorescent myelin staining and myelin basic protein (MBP) immunostaining; and mRNA and protein levels of NLRP3 inflammasome complex proteins were measured by quantitative real-time PCR and Western blot, respectively. Additionally, serum and brain levels of IL-1β and -18 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were determined by enzyme-linked immunosorbent assay. It was found that HBO2 improved learning and memory, and alleviated myelin injury in mice subjected to acute CO exposure. Furthermore, HBO2 decreased NLRP3, absent in melanoma 2 (AIM2), caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain mRNA and protein levels, and reduced brain and serum concentrations of IL-1β and -18 and NADPH oxidase. These results indicate that HBO2 suppresses the inflammatory response after ACOP by blocking NLRP3 inflammasome activation, thereby alleviating cognitive deficits.

Neuroinflammation plays an important role in brain damage after acute carbon monoxide poisoning (ACOP). The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing (NLRP) 3 inflammasome triggers the activation of inflammatory caspases and maturation of interleukin (IL)-1β and -18, and has been linked to various human autoinflammatory and autoimmune diseases. In this study we investigated the effects of hyperbaric oxygen (HBO2) on NLRP3 inflammasome activation after ACOP. Mice were randomly divided into four groups: sham group (exposure to normobaric air - i.e., 21% O2 at 1 atmosphere absolute); HBO2-only group; CO + normobaric air group; and CO + HBO2 group. Cognitive function was evaluated with the Morris water maze; myelin injury was assessed by FluoroMyelin GreenTM fluorescent myelin staining and myelin basic protein (MBP) immunostaining; and mRNA and protein levels of NLRP3 inflammasome complex proteins were measured by quantitative real-time PCR and Western blot, respectively. Additionally, serum and brain levels of IL-1ββ and -18 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were determined by enzyme-linked immunosorbent assay. It was found that HBO2 improved learning and memory, and alleviated myelin injury in mice subjected to acute CO exposure. Furthermore, HBO2 decreased NLRP3, absent in melanoma 2 (AIM2), caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain mRNA and protein levels, and reduced brain and serum concentrations of IL-1β and -18 and NADPH oxidase. These results indicate that HBO2 suppresses the inflammatory response after ACOP by blocking NLRP3 inflammasome activation, thereby alleviating cognitive deficits.

Previous genetic fate-mapping studies have indicated that embryonic glial fibrillary acidic protein-positive (GFAP(+)) cells are multifunctional progenitor/neural stem cells that can produce astrocytes as well as neurons and oligodendrocytes throughout the adult mouse central nervous system (CNS). However, emerging evidence from recent studies indicates that GFAP(+) cells adopt different cell fates and generate different cell types in different regions. Moreover, the fate of GFAP(+) cells in the young adult mouse CNS is not well understood. In the present study, hGFAP-Cre/R26R transgenic mice were used to investigate the lineage of embryonic GFAP(+) cells in the young adult mouse CNS. At postnatal day 21, we found that GFAP(+) cells mainly generated NeuN(+) neurons in the cerebral cortex (both ventral and dorsal), hippocampus, and cerebellum. Strangely, these cells were negative for the Purkinje cell marker calbindin in the cerebellum and the neuronal marker NeuN in the thalamus. Thus, contrary to previous studies, our genetic fate-mapping revealed that the cell fate of embryonic GFAP(+) cells at the young adult stage is significantly different from that at the adult stage.

Neural progenitors/stem cells (NSCs) exist in neonatal mouse subventricular zone (SVZ). To explore the differentiation of the NSCs in neonatal mouse SVZ and the distribution of the progeny cells derived from these NSCs in early adulthood, the enhanced green fluorescent protein (EGFP) plasmid was transferred into the NSCs in the lateral ventricle of newborn mice (P0) by in-vivo electroporation to trace these cells and their progeny cells. Thirty days after electroporation, histological sections of mouse brain were prepared for immunofluorescence with cell-specific antibodies to identify the type(s) of cells that were marked by EGFP. The results showed that EGFP-positive cells were distributed mainly in the olfactory bulb (OB), cortex, and SVZ, and double labeled with NeuN (neuron marker) in OB, glial fibrillary acidic protein (GFAP) (astrocyte marker) in the cortex, and Blbp and GFAP (astrocyte marker) in SVZ. However, there was no-EGFP-positive cell in the hippocampus. The present results indicate that the NSCs in SVZ of the neonatal mouse can give rise to neurons in the OB and astrocytes in the cortex in early adulthood, but not generate progeny cells residing in the hippocampus. In addition, there are still neural progenitors in SVZ until early adulthood.