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Autism spectrum disorder (ASD) has become one of the most common neurological developmental disorders in children. However, the study of ASD diagnostic markers faces significant challenges due to the existence of heterogeneity. In this study, genetic testing was performed on children who were clinically diagnosed with ASD. Children with ASD susceptibility genes and healthy controls were studied. The proteomics of plasma and peripheral blood mononuclear cells (PBMCs) as well as plasma metabolomics were carried out. The results showed that although there was genetic heterogeneity in children with ASD, the differentially expressed proteins (DEPs) in plasma, peripheral blood mononuclear cells, and differential metabolites in plasma could still effectively distinguish autistic children from controls. The mechanism associated with them focuses on several common and previously reported mechanisms of ASD. The biomarkers for ASD diagnosis could be found by taking differentially expressed proteins and differential metabolites into consideration. Integrating omics data, glycerophospholipid metabolism and N-glycan biosynthesis might play a critical role in the pathogenesis of ASD.

Existing data demonstrate a significant correlation between autism spectrum disorder (ASD) and the status of biologically essential and toxic trace elements. However, there is still a lack of data on the steady state of trace elements in ASD. We performed a case-control study to explore the association between the risk of ASD and 23 trace elements in plasma. The results showed that children with ASD had considerably decreased lithium (Li), manganese (Mn), selenium (Se), barium (Ba), mercury (Hg), and tin (Sn) levels when compared to their age- and sex-matched controls. Meanwhile, children with ASD had considerably increased plasma chromium (Cr) and vanadium (V) concentrations. We also divided each group into subgroups based on age and gender and created element-related networks for each subgroup. We detected significant element correlations within or between subgroups, as well as changes in correlations that included all elements examined. Finally, more element correlations were observed among males, which may open a new avenue for understanding the complicated process behind the sex ratio of children with ASD. Overall, our data revealed a novel relationship between elements and ASD, which may extend current understanding about ASD.

Arsenic (As) exposure is a major public health challenge worldwide. Much evidence suggests that As exposure can cause disturbances in trace element balance in the body. However, there are few reports on the effect of As on trace element levels in the central nervous system (CNS). We conducted an experiment to detect 19 elements in the hippocampus and cortex of arsenic-exposed rats by inductively coupled plasma mass spectrometry. The results showed that As levels in the hippocampus and cortex of arsenic-exposed rats were significantly higher than those in the control group, and As levels in the cortex were significantly higher than that in the hippocampus. In the hippocampus of arsenic-exposed group, the levels of Cd, Ho and Rb increased, while the levels of Au, Ba, Ce, Cs, Pd, Se, Sr and Tl decreased; In cortex, the levels of Cd and Rb increased, and the levels of Se and Au decreased. There were significant sex differences in the effects of As on Cd, Ba, Rb and Sr in the hippocampus and on Cd and Mo in the cortex. It is suggested that elemental imbalance may be a risk factor for the development of As toxicity and is closely associated with arsenic-induced CNS damage.

Chronic arsenic poisoning is a global health problem that affects millions of people, and studies have found that long-term ingestion of arsenic-containing compounds can lead to lung damage, but the exact mechanism is unknown. In this study, Sprague-Dawley (SD) rats were used as the research object, and the proteomic analysis method based on sequential window acquisition of all theoretical fragment ions (SWATH) was used to detect the changes in the expression levels of related proteins in the lung tissue of arsenic-exposed rats, and to explore the mechanism of arsenic compound-induced lung injury. The results showed that arsenic exposure resulted in the abnormal expression of collagen type III and proteins involved in metabolic, immune, and cellular processes, leading to the dysfunction of important pathways associated with these proteins, resulting in lung injury. It suggested that the underlying mechanism of arsenic-induced lung injury may be related to oxidative stress, immune injury, cell junction, and collagen type III. This result provides a new research idea for revealing the mechanism of lung injury caused by arsenic exposure.

Article, 信州医学雑誌 69(1): 45-52(2021)

CRISPR/Cas9-mediated gene knock-in in in vivo neurons using in utero electroporation is a powerful technique, but the knock-in efficiency is generally low. We previously demonstrated that co-transfection with RAD51, a key molecule of the initial step of homology-directed repair (HDR), expression vector increased EGFP knock-in efficiency in the β-actin site up to 2.5-fold in the pyramidal neurons in layer 2/3 of the somatosensory cortex of mouse brain. To further improve the efficiency, we examined the effect of inhibition of DNA ligase IV (LIG4) that is an essential molecule for non-homologous end joining (NHEJ). Co-transfection with small hairpin RNA for LIG4 (shlig4) expression vector increased the EGFP knock-in efficiency in the β-actin site up to 3.6-fold compared to the condition without shlig4. RAD51 and shlig4 expression vector co-transfection further increased the knock-in efficiency up to 4.7-fold of the control condition. These results suggest that the inhibition of LIG4 is more effective than RAD51 overexpression, and it enhances the effect of RAD51 overexpression on HDR-mediated gene knock-in in vivo neurons.

Autism spectrum disorder (ASD) is a neurological and developmental disorder characterized by social and communication difficulties. Valproic acid (VPA) injection during pregnancy elicits autism-like behavior in the offspring, making it a classic animal model of ASD. However, the mechanisms involved have not yet been determined. In this study, we used iTRAQ (isobaric tags for relative and absolute quantification) proteomics analysis of the cerebral cortex of a VPA rat model (VPA group) and controls (CON group). The results showed that 79 differentially expressed proteins (DEPs) were identified between the VPA group and the CON group. Based on bioinformatics analysis, the DEPs were mainly enriched at synapses, especially glutamatergic synapses and GABAergic synapses. Some DEPs were involved in energy metabolism, thyroid hormone synthesis pathway, and Na

Background: Autism spectrum disorder (ASD) has become one of the most common neurological developmental disorders in children. However, the study of ASD diagnostic markers faces significant challenges due to the existence of heterogeneity. Methods: In this study, genetic testing was performed on children who were clinically diagnosed with ASD. Children with ASD susceptibility genes and healthy controls were studied. The proteomics of plasma and peripheral blood mononuclear cells (PBMCs) as well as plasma metabolomics were carried out. Results: The results showed that although there was genetic heterogeneity in children with ASD, the differentially expressed proteins (DEPs) in plasma, PBMCs, and differential metabolites in plasma could still effectively distinguish autistic children from controls. The mechanism associated with them focus on several common and previously reported mechanisms of ASD. Limitations: The number of samples carrying risk genes in omics research is limited. In further research, a large sample size is required. A group of children who have been diagnosed with ASD but have not been detected to carry risk genes should also be included.Conclusion: The biomarkers for ASD diagnosis could be found by taking DEPs and differential metabolites into consideration. Integrating omics data, glycerophospholipid metabolism and N-glycan biosynthesis might play a critical role in the pathogenesis of ASD.

IQSEC3, a gephyrin-binding GABAergic (gamma-aminobutyric acidergic) synapse-specific guanine nucleotide exchange factor, was recently reported to regulate activity-dependent GABAergic synapse maturation, but the underlying signaling mechanisms remain incompletely understood.We generated mice with conditional knockout (cKO) of Iqsec3 to examine whether altered synaptic inhibition influences hippocampus-dependent fear memory formation. In addition, electrophysiological recordings, immunohistochemistry, and behavioral assays were used to address our question.We found that Iqsec3-cKO induces a specific reduction in GABAergic synapse density, GABAergic synaptic transmission, and maintenance of long-term potentiation in the hippocampal CA1 region. In addition, Iqsec3-cKO mice exhibited impaired fear memory formation. Strikingly, Iqsec3-cKO caused abnormally enhanced activation of ribosomal P70-S6K1-mediated signaling in the hippocampus but not in the cortex. Furthermore, inhibiting upregulated S6K1 signaling by expressing dominant-negative S6K1 in the hippocampal CA1 of Iqsec3-cKO mice completely rescued impaired fear learning and inhibitory synapse density but not deficits in long-term potentiation maintenance. Finally, upregulated S6K1 signaling was rescued by IQSEC3 wild-type, but not by an ARF-GEF (adenosine diphosphate ribosylation factor-guanine nucleotide exchange factor) inactive IQSEC3 mutant.Our results suggest that IQSEC3-mediated balanced synaptic inhibition in hippocampal CA1 is critical for the proper formation of hippocampus-dependent fear memory.

The Fe–H system demonstrates a complex phase diagram and diverse electronic properties under high pressure. Ni has a similar electronic configuration to Fe, showing similar and different chemical p...

Neurexins and neuroligins are two distinct families of single-pass transmembrane proteins localized at pre- and postsynapses, respectively. They trans-synaptically interact with each other and induce synapse formation and maturation. Common variants and rare mutations, including copy number variations, short deletions, and single or small nucleotide changes in neurexin and neuroligin genes have been linked to the neurodevelopmental disorders, such as autism spectrum disorders (ASDs). In this review, we summarize the structure and basic synaptic function of neurexins and neuroligins, followed by behaviors and synaptic phenotypes of knock-in and knock-out mouse of these family genes. From the studies of these mice, it turns out that the effects of neurexins and neuroligins are amazingly neural circuit dependent, even within the same brain region. In addition, neurexins and neuroligins are commonly involved in the endocannabinoid signaling. These finding may provide not only insight into understanding the pathophysiology, but also the concept for strategy of therapeutic intervention for ASDs.

Calcium/calmodulin-dependent serine protein kinase (CASK) is a membrane-associated guanylate kinase (MAGUK) protein that is associated with neurodevelopmental disorders. CASK is thought to have both pre- and postsynaptic functions, but the mechanism and consequences of its functions in the brain have yet to be elucidated, because homozygous CASK-knockout (CASK-KO) mice die before brain maturation. Taking advantage of the X-chromosome inactivation (XCI) mechanism, here we examined the synaptic functions of CASK-KO neurons in acute brain slices of heterozygous CASK-KO female mice. We also analyzed CASK-knockdown (KD) neurons in acute brain slices generated by in utero electroporation. Both CASK-KO and CASK-KD neurons showed a disruption of the excitatory and inhibitory (E/I) balance. We further found that the expression level of the N-methyl-D-aspartate receptor subunit GluN2B was decreased in CASK-KD neurons and that overexpressing GluN2B rescued the disrupted E/I balance in CASK-KD neurons. These results suggest that the down-regulation of GluN2B may be involved in the mechanism of the disruption of synaptic E/I balance in CASK-deficient neurons.