Suv39h1 regulates memory stability by inhibiting the expression of Shank1 in hippocampal newborn neurons.

Adult newborn neurons are involved in memory encoding and extinction, but the neural mechanism is unclear. We found the adult newborn neurons at 4 weeks are recruited by learning and subjected to epigenetic regulations, consequently reducing their ability to be re-recruited later. After removal of the epigenetic blockage, Suv39h1 KO mice showed an increased recruiting number of aged newborn neurons and enhanced flexibility in learning tasks. Besides NRXN1, we found SHANK1, the synaptic scaffold protein, is one of the major targets of Suv39h1, regulating memory stability. Expression of Shank1 is transiently engaged to enhance synaptogenesis during learning and is strongly suppressed by Suv39h1 from 5 h after learning. Exogenously overexpression of Shank1 in dentate gyrus increased the density of mushroom spines and decreased the persistency of old memories. Our study indicated the activity-regulated epigenetic modification in newly matured newborn neurons in hippocampus insulates temporally distinct experiences and stabilizes old memories.

A sensitive cholesterol electrochemical biosensor based on biomimetic cerasome and graphene quantum dots.

A simple and sensitive electrochemical cholesterol biosensor was fabricated based on ceramic-coated liposome (cerasome) and graphene quantum dots (GQDs) with good conductivity. The cerasome consists of a lipid-bilayer membrane and a ceramic surface as a soft biomimetic interface, and the mild layer-by-layer self-assembled method as the immobilization strategy on the surface of the modified electrode was used, which can provide good biocompatibility to maintain the biological activity of cholesterol oxidase (ChOx). The GQDs promoted electron transport between the enzyme and the electrode more effectively. The structure of the cerasome-forming lipid was characterized by Fourier transform infrared (FT-IR). The morphology and characteristics of the cerasome and GQDs were characterized by transmission electron microscopy (TEM), zeta potential, photoluminescence spectra (PL), etc. The proposed biosensors revealed excellent catalytic performance to cholesterol with a linear concentration range of 16.0 × 10-6-6.186 × 10-3 mol/L, with a low detection limit (LOD) of 5.0 × 10-6 mol/L. The Michaelis-Menten constant (Km) of ChOx was 5.46 mmol/L, indicating that the immobilized ChOx on the PEI/GQDs/PEI/cerasome-modified electrode has a good affinity to cholesterol. Moreover, the as-fabricated electrochemical biosensor exhibited good stability, anti-interference ability, and practical application for cholesterol detection.

Mutations in ASH1L confer susceptibility to Tourette syndrome.

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l+/- mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.

Asymmetric ultrathin silica nanonets as a super-performance emulsifier.

HYPOTHESIS: Pickering emulsions have been used in many fields such as catalytic synthesis, pharmaceutics and oilfield chemicals. They usually have good stability, but in some extreme conditions such as at high temperatures or in special liquid-liquid systems, poor stability is often encountered. EXPERIMENTS: Herein, ultrathin silica nanosheets with controllable morphologies were synthesized via a simple interfacial anisotropic self-assembly approach integrated with pore-forming techniques. By regulating the size, density and pattern of the apertures, three types of unique nanosheets including mesoporous nanosheets, meso/macroporous topology-nanosheets and asymmetric nanonets with hollows were obtained. FINDINGS: After a simple hydrophobic modification, the nanonets exhibited super-performance as particulate emulsifiers, owing to their two-dimensional (2D) structures of large pore volume and hierarchical pore/hollow arrangements. As a result, those silica nanonets can stabilize various emulsion systems at considerably high temperatures that are difficult to be stabilized by conventional particulate emulsifiers even at a dose of 100x higher. This work paves a promising way to develop novel 2D asymmetric nanomaterials with tunable compositions, aperture parameters and morphologies for emulsification and potential applications.

ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder.

ASD-associated genes are enriched for synaptic proteins and epigenetic regulators. How those chromatin modulators establish ASD traits have remained unknown. We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior, including repetitive behavior, and alters social behavior. Specific depletion of Ash1l in forebrain induces similar ASD-associated behavioral defects. While the learning ability remains intact, the discrimination ability of Ash1l mutant mice is reduced. Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period. Dysregulation of synaptic genes is detected in Ash1l mutant brain. Specifically, Eph receptor A7 is downregulated in Ash1l+/- mice through accumulating EZH2-mediated H3K27me3 in its gene body. Importantly, increasing activation of EphA7 in Ash1l+/- mice by supplying its ligand, ephrin-A5, strongly promotes synapse pruning and rescues discrimination deficits. Our results suggest that Ash1l haploinsufficiency is a highly penetrant risk factor for ASD, resulting from synapse pruning deficits.

Egr1-EGFP transgenic mouse allows in vivo recording of Egr1 expression and neural activity.

BACKGROUND: Immediate-early genes (IEGs) have been serving as markers of active neurons for their rapid responses to stimulation. With the development of IEG-EGFP reporters by the GENSAT project, application of the IEGs have been greatly expanded. However, detailed validations for these systems are still lacking, causing trouble in the interpretation of the fluorescence signals. NEW METHOD: In this work, taken Egr1-EGFP transgenic mice as an example, we proposed an improvement for the usage of the Egr1-EGFP reporter system based on detailed validation of its fluorescence signals. RESULTS: Firstly, the exogenous EGFP mRNA levels were linearly correlated with the endogenous Egr1 mRNA levels in neurons. Secondly, the 3-hr-changes of the Egr1-EGFP signals before and after the stimulus were positively correlated with the stimulus-induced neuronal activities. Interestingly, persistent neuronal activity patterns in the post-stimulus phase also showed correlation with the stimulus-induced Egr1-EGFP signal changes. Furthermore, enriched environments engaged dramatic neuronal activations, allowing detailed characterization of Egr1-EGFP expression dynamics. COMPARISON WITH EXISTING METHOD(S): People used to infer the neuronal activities based on the raw fluorescence signals of IEG-EGFP reporter system, which was strongly obstructed by distinct protein regulation or dynamic properties between the EGFP and the IEGs. We demonstrated a better way for data analysis and experimental design. CONCLUSIONS: Taken together, this work proves that Egr1-EGFP signal is weakly but significantly correlated to task-induced neural activity and gives detailed characterization of the signal dynamics. It not only provides basis for the understanding of the IEG-EGFP fluorescence signals but also offers instructions for proper experimental design with IEG-EGFP reporter systems.

Ionic liquid functionalized Janus nanosheets.

Ionic liquid functionalized Janus nanosheets are synthesized by selective treatment of the imidazolin terminated side of Janus nanosheets while the other side is preserved. The Janus performance of the nanosheets and thus emulsion stability are reversibly triggered by anion exchange.