Publications by authors named "Takeo Yoshikawa"

276 Publications

A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain.

Mol Psychiatry 2021 Jul 15. Epub 2021 Jul 15.

Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan.

Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) dimethylation resulting from genetic variants in histone methyltransferases is known for neurodevelopmental and behavioral anomalies. However, a systematic examination of H3K9 methylation dynamics in ASD is lacking. Here we resequenced nine genes for histone methyltransferases and demethylases involved in H3K9 methylation in individuals with ASD and healthy controls using targeted next-generation sequencing. We identified a novel rare variant (A211S) in the SUV39H2, which was predicted to be deleterious. The variant showed strongly reduced histone methyltransferase activity in vitro. In silico analysis showed that the variant destabilizes the hydrophobic core and allosterically affects the enzyme activity. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which is relevant for ASD. The Suv39h2 deficit evoked an elevated expression of a subset of protocadherin β (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. Reduced H3K9me3 persisted in the cerebellum of Suv39h2-deficient mice to an adult stage. Congruently, reduced expression of SUV39H1 and SUV39H2 in the postmortem brain samples of ASD individuals was observed, underscoring the role of H3K9me3 deficiency in ASD etiology. The present study provides direct evidence for the role of SUV39H2 in ASD and suggests a molecular cascade of SUV39H2 dysfunction leading to H3K9me3 deficiency followed by an untimely, elevated expression of Pcdhb cluster genes during early neurodevelopment.
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http://dx.doi.org/10.1038/s41380-021-01199-7DOI Listing
July 2021

Abnormal gene expression of BDNF, but not BDNF-AS, in iPSC, neural stem cells and postmortem brain samples from bipolar disorder.

J Affect Disord 2021 07 3;290:61-64. Epub 2021 May 3.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Electronic address:

Background: Brain-derived neurotrophic factor (BDNF) antisense RNA (BDNF-AS) was identified as naturally conserved non-coding antisense RNA that suppresses the transcription of BDNF.

Methods: We measured the expression of BDNF mRNA and BDNF-AS mRNA in iPSC and NSC from bipolar disorder (BD) patients and healthy control subjects, and postmortem brain samples such as the corpus callosum, the Brodmann area (BA8), and BA46 from BD patients and age- and sex-matched controls.

Results: The expression of BDNF mRNA in iPSC from BD patients (n = 6) was significantly lower than that of control subjects (n = 4) although the expression of BDNF mRNA in NSC from BD patients was significantly higher than that of control subjects. In contrast, there were no changes in the expression of BDNF-AS mRNA in both iPSC and NSC between two groups. The expression of BDNF mRNA in the BA46 from BD patients (n = 35) was significantly lower than that of controls (n = 34) although the expression of BDNF mRNA in the corpus callosum and BA8 was not different between two groups (n = 15). In contrast, there were no changes in expression of BDNF-AS mRNA in the three brain regions between two groups. Interestingly, there were significant positive correlations between BDNF mRNA expression and BDNF-AS mRNA expression in the postmortem brain samples.

Limitations: Sample sizes are relatively low.

Conclusions: Our data suggest that abnormalities in the expression of BDNF, but not BDNF-AS, play a role in the pathogenesis of BD.
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http://dx.doi.org/10.1016/j.jad.2021.04.042DOI Listing
July 2021

Glyoxalase I disruption and external carbonyl stress impair mitochondrial function in human induced pluripotent stem cells and derived neurons.

Transl Psychiatry 2021 05 8;11(1):275. Epub 2021 May 8.

Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.

Carbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, we found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger. Our observations can be used for designing an intervention strategy for diseases, particularly those induced by enhanced carbonyl stress or oxidative stress.
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http://dx.doi.org/10.1038/s41398-021-01392-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106684PMC
May 2021

Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport.

Cell Rep 2021 Apr;35(2):108971

Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan. Electronic address:

In schizophrenia (SCZ), neurons in the brain tend to undergo gross morphological changes, but the related molecular mechanism remains largely elusive. Using Kif3b mice as a model with SCZ-like behaviors, we found that a high-betaine diet can significantly alleviate schizophrenic traits related to neuronal morphogenesis and behaviors. According to a deficiency in the transport of collapsin response mediator protein 2 (CRMP2) by the KIF3 motor, we identified a significant reduction in lamellipodial dynamics in developing Kif3b neurons as a cause of neurite hyperbranching. Betaine administration significantly decreases CRMP2 carbonylation, which enhances the F-actin bundling needed for proper lamellipodial dynamics and microtubule exclusion and may thus functionally compensate for KIF3 deficiency. Because the KIF3 expression levels tend to be downregulated in the human prefrontal cortex of the postmortem brains of SCZ patients, this mechanism may partly participate in human SCZ pathogenesis, which we hypothesize could be alleviated by betaine administration.
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http://dx.doi.org/10.1016/j.celrep.2021.108971DOI Listing
April 2021

Cooperation of LIM domain-binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia.

EMBO Mol Med 2021 Apr 3;13(4):e12574. Epub 2021 Mar 3.

Laboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.

Genomic defects with large effect size can help elucidate unknown pathologic architecture of mental disorders. We previously reported on a patient with schizophrenia and a balanced translocation between chromosomes 4 and 13 and found that the breakpoint within chromosome 4 is located near the LDB2 gene. We show here that Ldb2 knockout (KO) mice displayed multiple deficits relevant to mental disorders. In particular, Ldb2 KO mice exhibited deficits in the fear-conditioning paradigm. Analysis of the amygdala suggested that dysregulation of synaptic activities controlled by the immediate early gene Arc is involved in the phenotypes. We show that LDB2 forms protein complexes with known transcription factors. Consistently, ChIP-seq analyses indicated that LDB2 binds to > 10,000 genomic sites in human neurospheres. We found that many of those sites, including the promoter region of ARC, are occupied by EGR transcription factors. Our previous study showed an association of the EGR family genes with schizophrenia. Collectively, the findings suggest that dysregulation in the gene expression controlled by the LDB2-EGR axis underlies a pathogenesis of subset of mental disorders.
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http://dx.doi.org/10.15252/emmm.202012574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033514PMC
April 2021

Organic Cation Transporters in Brain Histamine Clearance: Physiological and Psychiatric Implications.

Handb Exp Pharmacol 2021 Feb 28. Epub 2021 Feb 28.

Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Histamine acts as a neurotransmitter in the central nervous system and is involved in numerous physiological functions. Recent studies have identified the causative role of decreased histaminergic systems in various neurological disorders. Thus, the brain histamine system has attracted attention as a therapeutic target to improve brain function. Neurotransmitter clearance is one of the most important processes for the regulation of neuronal activity and is an essential target for diverse drugs. Our previous study has shown the importance of histamine N-methyltransferase for the inactivation of brain histamine and the intracellular localization of this enzyme; the study indicated that the transport system for the movement of positively charged histamine from the extracellular to intracellular space is a prerequisite for histamine inactivation. Several studies on in vitro astrocytic histamine transport have indicated the contribution of organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) in histamine uptake, although the importance of these transporters in in vivo histamine clearance remains unknown. Immunohistochemical analyses have revealed the expression of OCT3 and PMAT on neurons, emphasizing the importance of investigating neuronal histamine uptake. Further studies using knockout mice or fast-scan cyclic voltammetry will accelerate the research on histamine transporters. In this review article, we summarize histamine transport assays and describe the candidate transporters responsible for histamine transport in the brain.
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http://dx.doi.org/10.1007/164_2021_447DOI Listing
February 2021

Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition, and Implication of CDH23 in Schizophrenia.

Schizophr Bull 2021 Jul;47(4):1190-1200

Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan.

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.
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http://dx.doi.org/10.1093/schbul/sbab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266601PMC
July 2021

Potential involvement of DSCAML1 mutations in neurodevelopmental disorders.

Genes Cells 2021 Mar 18;26(3):136-151. Epub 2021 Feb 18.

Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan.

The molecular mechanisms underlying neurodevelopmental disorders (NDDs) remain unclear. We previously identified Down syndrome cell adhesion molecule like 1 (Dscaml1) as a responsible gene for Ihara epileptic rat (IER), a rat model for human NDDs with epilepsy. However, the relationship between NDDs and DSCAML1 in humans is still elusive. In this study, we screened databases of autism spectrum disorders (ASD), intellectual disability (ID)/developmental disorders (DD) and schizophrenia for genomic mutations in human DSCAML1. We then performed in silico analyses to estimate the potential damage to the mutated DSCAML1 proteins and chose three representative mutations (DSCAML1 , DSCAML1 and DSCAML1 ), which lacked a cysteine residue in the seventh Ig domain, the intracellular region and the C-terminal PDZ-binding motif, respectively. In overexpression experiments in a cell line, DSCAML1 lost its mature N-glycosylation, whereas DSCAML1 was abnormally degraded via proteasome-dependent protein degradation. Furthermore, in primary hippocampal neurons, the ability of the wild-type DSCAML1 to regulate the number of synapses was lost with all mutant proteins. These results provide insight into understanding the roles of the domains in the DSCAML1 protein and further suggest that these mutations cause functional changes, albeit through different mechanisms, that likely affect the pathophysiology of NDDs.
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http://dx.doi.org/10.1111/gtc.12831DOI Listing
March 2021

Peroxisome proliferator-activated receptor α as a novel therapeutic target for schizophrenia.

EBioMedicine 2020 Dec 2;62:103130. Epub 2020 Dec 2.

Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan; Department of Biological Science, Graduate School of Humanities and Science, Ochanomizu University, Tokyo 112-8610, Japan. Electronic address:

Background: The pathophysiology of schizophrenia, a major psychiatric disorder, remains elusive. In this study, the role of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor (RXR) families, belonging to the ligand-activated nuclear receptor superfamily, in schizophrenia, was analyzed.

Methods: The PPAR/RXR family genes were screened by exploiting molecular inversion probe (MIP)-based targeted next-generation sequencing (NGS) using the samples of 1,200 Japanese patients with schizophrenia. The results were compared with the whole-genome sequencing databases of the Japanese cohort (ToMMo) and the gnomAD. To reveal the relationship between PPAR/RXR dysfunction and schizophrenia, Ppara KO mice and fenofibrate (a clinically used PPARα agonist)-administered mice were assessed by performing behavioral, histological, and RNA-seq analyses.

Findings: Our findings indicate that c.209-2delA, His117Gln, Arg141Cys, and Arg226Trp of the PPARA gene are risk variants for schizophrenia. The c.209-2delA variant generated a premature termination codon. The three missense variants significantly decreased the activity of PPARα as a transcription factor in vitro. The Ppara KO mice exhibited schizophrenia-relevant phenotypes, including behavioral deficits and impaired synaptogenesis in the cerebral cortex. Oral administration of fenofibrate alleviated spine pathology induced by phencyclidine, an N-methyl-d-aspartate (NMDA) receptor antagonist. Furthermore, pre-treatment with fenofibrate suppressed the sensitivity of mice to another NMDA receptor antagonist, MK-801. RNA-seq analysis revealed that PPARα regulates the expression of synaptogenesis signaling pathway-related genes.

Interpretation: The findings of this study indicate that the mechanisms underlying schizophrenia pathogenesis involve PPARα-regulated transcriptional machinery and modulation of synapse physiology. Hence, PPARα can serve as a novel therapeutic target for schizophrenia.
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http://dx.doi.org/10.1016/j.ebiom.2020.103130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728824PMC
December 2020

Down syndrome cell adhesion molecule like-1 (DSCAML1) links the GABA system and seizure susceptibility.

Acta Neuropathol Commun 2020 11 30;8(1):206. Epub 2020 Nov 30.

Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8502, Japan.

The Ihara epileptic rat (IER) is a mutant model with limbic-like seizures whose pathology and causative gene remain elusive. In this report, via linkage analysis, we identified Down syndrome cell adhesion molecule-like 1(Dscaml1) as the responsible gene for IER. A single base mutation in Dscaml1 causes abnormal splicing, leading to lack of DSCAML1. IERs have enhanced seizure susceptibility and accelerated kindling establishment. Furthermore, GABAergic neurons are severely reduced in the entorhinal cortex (ECx) of these animals. Voltage-sensitive dye imaging that directly presents the excitation status of brain slices revealed abnormally persistent excitability in IER ECx. This suggests that reduced GABAergic neurons may cause weak sustained entorhinal cortex activations, leading to natural kindling via the perforant path that could cause dentate gyrus hypertrophy and epileptogenesis. Furthermore, we identified a single nucleotide substitution in a human epilepsy that would result in one amino acid change in DSCAML1 (A2105T mutation). The mutant DSCAML1 protein is not presented on the cell surface, losing its homophilic cell adhesion ability. We generated knock-in mice (Dscaml1) carrying the corresponding mutation and observed reduced GABAergic neurons in the ECx as well as spike-and-wave electrocorticogram. We conclude that DSCAML1 is required for GABAergic neuron placement in the ECx and suppression of seizure susceptibility in rodents. Our findings suggest that mutations in DSCAML1 may affect seizure susceptibility in humans.
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http://dx.doi.org/10.1186/s40478-020-01082-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706048PMC
November 2020

A potential role of fatty acid binding protein 4 in the pathophysiology of autism spectrum disorder.

Brain Commun 2020 10;2(2):fcaa145. Epub 2020 Sep 10.

Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama, Japan.

Autism spectrum disorder is a neurodevelopmental disorder characterized by difficulties in social communication and interaction, as well as repetitive and characteristic patterns of behaviour. Although the pathogenesis of autism spectrum disorder is unknown, being overweight or obesity during infancy and low weight at birth are known as risks, suggesting a metabolic aspect. In this study, we investigated adipose tissue development as a pathophysiological factor of autism spectrum disorder by examining the serum levels of adipokines and other metabolic markers in autism spectrum disorder children ( = 123) and typically developing children ( = 92) at 4-12 years of age. Among multiple measures exhibiting age-dependent trajectories, the leptin levels displayed different trajectory patterns between autism spectrum disorder and typically developing children, supporting an adipose tissue-dependent mechanism of autism spectrum disorder. Of particular interest, the levels of fatty acid binding protein 4 (FABP4) were significantly lower in autism spectrum disorder children than in typically developing subjects, at preschool age (4-6 years old:  = 21 for autism spectrum disorder and  = 26 for typically developing). The receiver operating characteristic curve analysis discriminated autism spectrum disorder children from typically developing children with a sensitivity of 94.4% and a specificity of 75.0%. We re-sequenced the exons of the gene in a Japanese cohort comprising 659 autism spectrum disorder and 1000 control samples, and identified two rare functional variants in the autism spectrum disorder group. The Trp98Stop, one of the two variants, was transmitted to the proband from his mother with a history of depression. The disruption of the gene in mice evoked autism spectrum disorder-like behavioural phenotypes and increased spine density on apical dendrites of pyramidal neurons, which has been observed in the postmortem brains of autism spectrum disorder subjects. The knockout mice had an altered fatty acid composition in the cortex. Collectively, these results suggest that an 'adipo-brain axis' may underlie the pathophysiology of autism spectrum disorder, with FABP4 as a potential molecule for use as a biomarker.
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http://dx.doi.org/10.1093/braincomms/fcaa145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667725PMC
September 2020

locus disruption on 4p16.1 as a risk factor for schizophrenia and bipolar disorder.

Hum Genome Var 2020 29;7:31. Epub 2020 Sep 29.

Schizophrenia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

We had previously reported the case of a male patient with schizophrenia, having de-novo balanced translocation. Here, we determined the exact breakpoints in chromosomes 4 and 13. The breakpoint within chromosome 4 was mapped to a region 32.6 kbp upstream of the LDB2 gene encoding Lim domain binding 2. Variant screening in revealed a rare novel missense variant in patients with psychiatric disorder.
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http://dx.doi.org/10.1038/s41439-020-00117-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524746PMC
September 2020

Lipid Pathology of the Corpus Callosum in Schizophrenia and the Potential Role of Abnormal Gene Regulatory Networks with Reduced Microglial Marker Expression.

Cereb Cortex 2021 Jan;31(1):448-462

Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan.

Structural changes in the corpus callosum have been reported in schizophrenia; however, the underlying molecular mechanism remains unclear. As the corpus callosum is high in lipid content, we analyzed the lipid contents of the corpora callosa from 15 patients with schizophrenia and 15 age- and sex-matched controls using liquid chromatography coupled to tandem mass spectrometry and identified lipid combinations associated with schizophrenia. Real-time quantitative polymerase chain reaction analyses using extended samples (schizophrenia, n = 95; control, n = 91) showed low expression levels of lipid metabolism-related genes and their potential upstream transcription factors in schizophrenia. Subsequent pathway analysis identified a gene regulatory network where nuclear factor of activated T cells 2 (NFATC2) is placed most upstream. We also observed low gene expression levels of microglial markers, inflammatory cytokines, and colony-stimulating factor 1 receptor (CSF1R), which is known to regulate the density of microglia, in the corpus callosum in schizophrenia. The interactions between CSF1R and several genes in the presently identified gene network originating from NFATC2 have been reported. Collectively, this study provides evidence regarding lipid abnormalities in the corpora callosa of patients with schizophrenia and proposes the potential role of impaired "NFATC2-relevant gene network-microglial axis" as its underlying mechanism.
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http://dx.doi.org/10.1093/cercor/bhaa236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727339PMC
January 2021

Fatty Acid Binding Protein 7 is Involved in the Proliferation of Reactive Astrocytes, but not in Cell Migration and Polarity.

Acta Histochem Cytochem 2020 Aug 4;53(4):73-81. Epub 2020 Jul 4.

Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

Reactive gliosis is a defense mechanism to minimize and repair the initial damage after CNS injuries that is characterized by increases in astrocytic reactivity and proliferation, with enhanced expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Fatty acid binding protein 7 (FABP7) is abundantly expressed in several types of glial cells, such as astrocytes and oligodendrocyte precursor cells, during brain development and FABP7-positive astrocytes have been shown to be significantly increased in the mouse cortex after a stab injury. However, the functional significance of FABP7 in gliosis remains unclear. In the present study, we examined the mechanism of FABP7-mediated regulation of gliosis using an scratch-injury model using primary cultured astrocytes. Western blotting showed that FABP7 expression was increased significantly in scratch wounded astrocytes at the edge of the injury compared with intact astrocytes. Through monitoring the occupancy of the injured area, FAB7-KO astrocytes showed a slower proliferation rate compared with WT astrocytes after 48 hr, which was confirmed by BrdU immunostaining. There were no differences in cell migration and polarity of reactive astrocytes between FABP-KO and WT. Conclusively, our data suggest that FABP7 is important in the proliferation of reactive astrocytes in the context of CNS injury.
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http://dx.doi.org/10.1267/ahc.20001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450179PMC
August 2020

FABP7 Regulates Acetyl-CoA Metabolism Through the Interaction with ACLY in the Nucleus of Astrocytes.

Mol Neurobiol 2020 Dec 19;57(12):4891-4910. Epub 2020 Aug 19.

Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.

Fatty acid binding protein 7 (FABP7) is an intracellular fatty acid chaperon that is highly expressed in astrocytes, oligodendrocyte-precursor cells, and malignant glioma. Previously, we reported that FABP7 regulates the response to extracellular stimuli by controlling the expression of caveolin-1, an important component of lipid raft. Here, we explored the detailed mechanisms underlying FABP7 regulation of caveolin-1 expression using primary cultured FABP7-KO astrocytes as a model of loss of function and NIH-3T3 cells as a model of gain of function. We discovered that FABP7 interacts with ATP-citrate lyase (ACLY) and is important for acetyl-CoA metabolism in the nucleus. This interaction leads to epigenetic regulation of several genes, including caveolin-1. Our novel findings suggest that FABP7-ACLY modulation of nuclear acetyl-CoA has more influence on histone acetylation than cytoplasmic acetyl-CoA. The changes to histone structure may modify caveolae-related cell activity in astrocytes and tumors, including malignant glioma.
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http://dx.doi.org/10.1007/s12035-020-02057-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541391PMC
December 2020

Heparan sulfate controls skeletal muscle differentiation and motor functions.

Biochim Biophys Acta Gen Subj 2020 12 15;1864(12):129707. Epub 2020 Aug 15.

Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.

Background: Heparan sulfate (HS) is a sulfated linear polysaccharide on cell surfaces that plays an important role in physiological processes. HS is present in skeletal muscles but its detailed role in this tissue remains unclear.

Methods: We examined the role of HS in the differentiation of C2C12 cells, a mouse myoblast cell line. We also phenotyped the impact of HS deletion in mouse skeletal muscles on their functions by using Cre-loxP system.

Results: CRISPR-Cas9-dependent HS deletion or pharmacological removal of HS dramatically impaired myoblast differentiation of C2C12 cells. To confirm the importance of HS in vivo, we deleted Ext1, which encodes an enzyme essential for HS biosynthesis, specifically in the mouse skeletal muscles (referred to as mExt1CKO mice). Treadmill and wire hang tests demonstrated that mExt1CKO mice exhibited muscle weakness. The contraction of isolated soleus muscles from mExt1CKO mice was also impaired. Morphological examination of mExt1CKO muscle tissue under light and electron microscopes revealed smaller cross sectional areas and thinner myofibrils. Finally, a model of muscle regeneration following BaCl injection into the tibialis anterior muscle of mice demonstrated that mExt1CKO mice had reduced expression of myosin heavy chain and an increased number of centronucleated cells. This indicates that muscle regeneration after injury was attenuated in the absence of HS expression in muscle cells.

Significance: These results demonstrate that HS plays an important role in skeletal muscle function by promoting differentiation.
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http://dx.doi.org/10.1016/j.bbagen.2020.129707DOI Listing
December 2020

Histaminergic neurons in the tuberomammillary nucleus as a control centre for wakefulness.

Br J Pharmacol 2021 02 15;178(4):750-769. Epub 2020 Sep 15.

Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Histamine plays pleiotropic roles as a neurotransmitter in the physiology of brain function, this includes the maintenance of wakefulness, appetite regulation and memory retrieval. Since numerous studies have revealed an association between histaminergic dysfunction and diverse neuropsychiatric disorders, such as Alzheimer's disease and schizophrenia, a large number of compounds acting on the brain histamine system have been developed to treat neurological disorders. In 2016, pitolisant, which was developed as a histamine H receptor inverse agonist by Schwartz and colleagues, was launched for the treatment of narcolepsy, emphasising the prominent role of brain histamine on wakefulness. Recent advances in neuroscientific techniques such as chemogenetic and optogenetic approaches have led to remarkable progress in the understanding of histaminergic neural circuits essential for the control of wakefulness. In this review article, we summarise the basic knowledge about the histaminergic nervous system and the mechanisms underlying sleep/wake regulation that are controlled by the brain histamine system. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc.
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http://dx.doi.org/10.1111/bph.15220DOI Listing
February 2021

VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction.

EBioMedicine 2020 Aug 30;58:102917. Epub 2020 Jul 30.

Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan; Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan. Electronic address:

Background: Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation.

Methods: An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses.

Findings: Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children.

Interpretation: Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology.

Funding: This study was supported mainly by MEXT, Japan.
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http://dx.doi.org/10.1016/j.ebiom.2020.102917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393524PMC
August 2020

Genetic risks of schizophrenia identified in a matched case-control study.

Eur Arch Psychiatry Clin Neurosci 2021 Jun 4;271(4):775-781. Epub 2020 Jul 4.

Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba, 260-8670, Japan.

It has been suggested that dopaminergic neurotransmission plays important roles for the psychotic symptoms and probably etiology of schizophrenia. In our recent preliminary study, we demonstrated that the specific allele combinations of dopamine-related functional single nucleotide polymorphisms (SNPs), rs10770141, rs4680, and rs1800497 could indicate risks for schizophrenia. The present validation study involved a total of 2542 individuals who were age- and sex-matched in a propensity score matching analysis, and the results supported the statistical significances of the proposed genetic risks described in our previous reports. The estimated odds ratios were 1.24 (95% CI 1.06-1.45, p < 0.001) for rs4680, 1.73 (95% CI 1.47-2.02, p < 0.0001) for rs1800497, and 1.79 (95% CI 1.35-2.36, p < 0.0001) for rs10770141. A significant relationship was also revealed among these three polymorphisms and schizophrenia, with corresponding coefficients (p < 0.0001). In this study, we also present a new scoring model for the identification of individuals with the disease risks. Using the cut-off value of 2, our model exhibited sensitivity for almost two-thirds of all of the schizophrenia patients: odds ratio 1.87, 95% CI 1.59-2.19, p < 0.0001. In conclusion, we identified significant associations of dopamine-related genetic combinations with schizophrenia. These findings suggest that some types of dopaminergic neurotransmission play important roles for development of schizophrenia, and this type of approach may also be applicable for other multifactorial diseases, providing a potent new risk predictor.
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http://dx.doi.org/10.1007/s00406-020-01158-3DOI Listing
June 2021

A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders.

Ann Clin Transl Neurol 2020 07 12;7(7):1117-1131. Epub 2020 Jun 12.

Department of Neurodevelopmental Disorder Genetics, Institute of Brain Science, Nagoya City University Graduate School of Medical Science, Nagoya, Aichi, 467-8601, Japan.

Objective: Neurodevelopmental disorders (NDDs) often associate with epilepsy or craniofacial malformations. Recent large-scale DNA analyses identified hundreds of candidate genes for NDDs, but a large portion of the cases still remain unexplained. We aimed to identify novel candidate genes for NDDs.

Methods: We performed exome sequencing of 95 patients with NDDs including 51 with trigonocephaly and subsequent targeted sequencing of additional 463 NDD patients, functional analyses of variant in vitro, and evaluations of autism spectrum disorder (ASD)-like phenotypes and seizure-related phenotypes in vivo.

Results: We identified de novo truncation variants in nine novel genes; CYP1A1, C14orf119, FLI1, CYB5R4, SEL1L2, RAB11FIP2, ZMYND8, ZNF143, and MSX2. MSX2 variants have been described in patients with cranial malformations, and our present patient with the MSX2 de novo truncation variant showed cranial meningocele and partial epilepsy. MSX2 protein is known to be ubiquitinated by an E3 ubiquitin ligase PJA1, and interestingly we found a PJA1 hemizygous p.Arg376Cys variant recurrently in seven Japanese NDD patients; five with trigonocephaly and one with partial epilepsy, and the variant was absent in 886 Japanese control individuals. Pja1 knock-in mice carrying p.Arg365Cys, which is equivalent to p.Arg376Cys in human, showed a significant decrease in PJA1 protein amount, suggesting a loss-of-function effect of the variant. Pja1 knockout mice displayed moderate deficits in isolation-induced ultrasonic vocalizations and increased seizure susceptibility to pentylenetetrazole.

Interpretation: These findings propose novel candidate genes including PJA1 and MSX2 for NDDs associated with craniofacial abnormalities and/or epilepsy.
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http://dx.doi.org/10.1002/acn3.51093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359110PMC
July 2020

Chronic brain histamine depletion in adult mice induced depression-like behaviours and impaired sleep-wake cycle.

Neuropharmacology 2020 09 6;175:108179. Epub 2020 Jun 6.

Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.

Histamine acts as a neurotransmitter to regulate various physiological processes. Brain histamine is synthesized from an essential amino acid histidine in a reaction catalysed by histidine decarboxylase (Hdc). Hdc-positive neurons exist mainly in the tuberomammillary nucleus (TMN) of the posterior hypothalamus and project their axons to the entire brain. Recent studies have reported that a chronic decrease in histamine levels in the adult human brain was observed in several neurological disorders. However, it is poorly understood whether lower histamine levels play a causative role in those disorders. In the present study, we induced chronic histamine deficiency in the brains of adult mice to allow direct interpretation of the relationship between an impaired histaminergic nervous system and the resultant phenotype. To induce chronic brain histamine deficiency starting in adulthood, adeno-associated virus expressing Cre recombinase was microinjected into the TMN of Hdc flox mice (cKO mice) at the age of 8 weeks. Immunohistochemical analysis showed expression of Cre recombinase in the TMN of cKO mice. The reduction of histamine contents with the decreased Hdc expression in cKO brain was also confirmed. Behavioural studies revealed that chronic histamine depletion in cKO mice induced depression-like behaviour, decreased locomotor activity in the home cage, and impaired aversive memory. Sleep analysis showed that cKO mice exhibited a decrease in wakefulness and increase in non-rapid eye movement sleep throughout the day. Taken together, this study clearly demonstrates that chronic histamine depletion in the adult mouse brain plays a causative role in brain dysfunction.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108179DOI Listing
September 2020

Betaine supplementation is associated with the resilience in mice after chronic social defeat stress: a role of brain-gut-microbiota axis.

J Affect Disord 2020 07 29;272:66-76. Epub 2020 Apr 29.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan. Electronic address:

Background: The brain-gut-microbiota axis plays a role in the pathogenesis of stress-related psychiatric disorders; however, its role in the resilience versus susceptibility after stress remains unclear. Dietary nutrient betaine is suggested to affect the gut microbiome. Here, we examined whether betaine supplementation can affect anhedonia-like phenotype in mice subjected to chronic social defeat stress (CSDS).

Methods: CSDS was performed during betaine supplementation. Sucrose preference test and 16S rRNA analysis of fecal samples were performed.

Results: CSDS did not produce an anhedonia-like phenotype in the betaine-treated mice, but did induce an anhedonia-like phenotype in water-treated mice. Furthermore, CSDS treatment did not alter the plasma levels of interleukin-6 (IL-6) of betaine-treated mice whereas CSDS caused higher plasma levels of IL-6 in water-treated mice. Betaine supplementation ameliorated the abnormal diversity and composition of the microbiota in the host gut after CSDS. At the genus level, CSDS caused marked increases in the several bacteria of water-treated mice, but not betaine-treated mice. CSDS increased levels of short-chain fatty acids (i.e., succinic acid and acetic acid) in feces from water-treated mice, but not betaine-treated mice. Interestingly, there are positive correlations between short-chain fatty acids (i.e., succinic acid, acetic acid, butyric acid) and several bacteria among the groups.

Limitations: Specific microbiome were not determined.

Conclusions: These findings suggest that betaine supplementation contributed to resilience to anhedonia in mice subjected to CSDS through anti-inflammation action. Therefore, it is likely that betaine could be a prophylactic nutrient to prevent stress-related psychiatric disorders.
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http://dx.doi.org/10.1016/j.jad.2020.03.095DOI Listing
July 2020

Evidence for Altered Metabolism of Sphingosine-1-Phosphate in the Corpus Callosum of Patients with Schizophrenia.

Schizophr Bull 2020 Apr 29. Epub 2020 Apr 29.

Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama, Japan.

The disturbed integrity of myelin and white matter, along with dysregulation of the lipid metabolism, may be involved in schizophrenia pathophysiology. Considering the crucial role of sphingolipids in neurodevelopment, particularly in oligodendrocyte differentiation and myelination, we examined the role of sphingolipid dynamics in the pathophysiology of schizophrenia. We performed targeted mass spectrometry-based analysis of sphingolipids from the cortical area and corpus callosum of postmortem brain samples from patients with schizophrenia and controls. We observed lower sphingosine-1-phosphate (S1P) levels, specifically in the corpus callosum of patients with schizophrenia, but not in major depressive disorder or bipolar disorder, when compared with the controls. Patient data and animal studies showed that antipsychotic intake did not contribute to the lowered S1P levels. We also found that lowered S1P levels in the corpus callosum of patients with schizophrenia may stem from the upregulation of genes for S1P-degrading enzymes; higher expression of genes for S1P receptors suggested a potential compensatory mechanism for the lowered S1P levels. A higher ratio of the sum of sphingosine and ceramide to S1P, which can induce apoptosis and cell-cycle arrest, was also observed in the samples of patients with schizophrenia than in controls. These results suggest that an altered S1P metabolism may underlie the deficits in oligodendrocyte differentiation and myelin formation, leading to the structural and molecular abnormalities of white matter reported in schizophrenia. Our findings may pave the way toward a novel therapeutic strategy.
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http://dx.doi.org/10.1093/schbul/sbaa052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505171PMC
April 2020

Histamine H receptor on astrocytes and neurons controls distinct aspects of mouse behaviour.

Sci Rep 2019 11 11;9(1):16451. Epub 2019 Nov 11.

Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.

Histamine is an important neurotransmitter that contributes to various processes, including the sleep-wake cycle, learning, memory, and stress responses. Its actions are mediated through histamine H-H receptors. Gene knockout and pharmacological studies have revealed the importance of H receptors in learning and memory, regulation of aggression, and wakefulness. H receptors are abundantly expressed on neurons and astrocytes. However, to date, studies selectively investigating the roles of neuronal and astrocytic H receptors in behaviour are lacking. We generated novel astrocyte- and neuron-specific conditional knockout (cKO) mice to address this gap in knowledge. cKO mice showed cell-specific reduction of H receptor gene expression. Behavioural assessment revealed significant changes and highlighted the importance of H receptors on both astrocytes and neurons. H receptors on both cell types played a significant role in anxiety. Astrocytic H receptors were involved in regulating aggressive behaviour, circadian rhythms, and quality of wakefulness, but not sleep behaviour. Our results emphasise the roles of neuronal H receptors in recognition memory. In conclusion, this study highlights the novel roles of H receptors on astrocytes and neurons in various brain functions.
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http://dx.doi.org/10.1038/s41598-019-52623-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848115PMC
November 2019

Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology.

EMBO Mol Med 2019 12 28;11(12):e10695. Epub 2019 Oct 28.

Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan.

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as-yet-unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H S)/polysulfide-producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst-deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst-transgenic (Tg) mice showed deteriorated PPI, suggesting that "sulfide stress" may be linked to PPI impairment. Analysis of human samples demonstrated that the H S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst-Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H S/polysulfides production.
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http://dx.doi.org/10.15252/emmm.201910695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895609PMC
December 2019

Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis.

Life Sci Alliance 2019 10 7;2(5). Epub 2019 Oct 7.

Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

Enhanced carbonyl stress underlies a subset of schizophrenia, but its causal effects remain elusive. Here, we elucidated the molecular mechanism underlying the effects of carbonyl stress in iPS cells in which the gene encoding zinc metalloenzyme glyoxalase I (), a crucial enzyme for the clearance of carbonyl stress, was disrupted. The iPS cells exhibited significant cellular and developmental deficits, and hyper-carbonylation of collapsing response mediator protein 2 (CRMP2). Structural and biochemical analyses revealed an array of multiple carbonylation sites in the functional motifs of CRMP2, particularly D-hook (for dimerization) and T-site (for tetramerization), which are critical for the activity of the CRMP2 tetramer. Interestingly, carbonylated CRMP2 was stacked in the multimer conformation by irreversible cross-linking, resulting in loss of its unique function to bundle microtubules. Thus, the present study revealed that the enhanced carbonyl stress stemmed from the genetic aberrations results in neurodevelopmental deficits through the formation of irreversible dysfunctional multimer of carbonylated CRMP2.
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http://dx.doi.org/10.26508/lsa.201900478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781483PMC
October 2019

Brain histamine H receptor occupancy after oral administration of desloratadine and loratadine.

Pharmacol Res Perspect 2019 08 12;7(4):e00499. Epub 2019 Jul 12.

Division of Pharmacology, Faculty of Medicine Tohoku Medical and Pharmaceutical University Sendai Japan.

Some histamine H receptor (HR) antagonists induce adverse sedative reactions caused by blockade of histamine transmission in the brain. Desloratadine is a second-generation antihistamine for treatment of allergic disorders. Its binding to brain HRs, which is the basis of sedative property of antihistamines, has not been examined previously in the human brain by positron emission tomography (PET). We examined brain HR binding potential ratio (BPR), HR occupancy (HRO), and subjective sleepiness after oral desloratadine administration in comparison to loratadine. Eight healthy male volunteers underwent PET imaging with [C]-doxepin, a PET tracer for HRs, after a single oral administration of desloratadine (5 mg), loratadine (10 mg), or placebo in a double-blind crossover study. BPR and HRO in the cerebral cortex were calculated, and plasma concentrations of loratadine and desloratadine were measured. Subjective sleepiness was quantified by the Line Analogue Rating Scale (LARS) and the Stanford Sleepiness Scale (SSS). BPR was significantly lower after loratadine administration than after placebo (0.504 ± 0.074 vs 0.584 ± 0.059 [mean ± SD], <0.05), but BPR after desloratadine administration was not significantly different from BPR after placebo (0.546 ± 0.084 vs 0.584 ± 0.059, = 0.250). The plasma concentration of loratadine was negatively correlated with BPR in subjects receiving loratadine, but that of desloratadine was not correlated with BPR. Brain HROs after desloratadine and loratadine administration were 6.47 ± 10.5% and 13.8 ± 7.00%, respectively (=0.103). Subjective sleepiness did not significantly differ among subjects receiving the two antihistamines and placebo. At therapeutic doses, desloratadine did not bind significantly to brain HRs and did not induce any significant sedation.
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http://dx.doi.org/10.1002/prp2.499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624455PMC
August 2019

Investigation of betaine as a novel psychotherapeutic for schizophrenia.

EBioMedicine 2019 Jul 26;45:432-446. Epub 2019 Jun 26.

Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama, Japan. Electronic address:

Background: Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. We aimed to test the role of betaine in schizophrenia pathophysiology, and to evaluate its potential as a novel psychotherapeutic.

Methods: Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses.

Findings: The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations in the brain. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine (PCP) treatments. Betaine also showed a prophylactic effect on behavioral abnormality induced by PCP. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with "betaine deficit-oxidative stress pathology". We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy.

Interpretation: The present study revealed the role of betaine in psychiatric pathophysiology and underscores the potential benefit of betaine in a subset of schizophrenia. FUND: This study was supported by the Strategic Research Program for Brain Sciences from AMED (Japan Agency for Medical Research and Development) under Grant Numbers JP18dm0107083 and JP19dm0107083 (TY), JP18dm0107129 (MM), JP18dm0107086 (YK), JP18dm0107107 (HY), JP18dm0107104 (AK) and JP19dm0107119 (KH), by the Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (TY), JP18H05433 (AH.-T), JP18H05428 (AH.-T and TY), and JP16H06277 (HY), and by JSPS KAKENHI under Grant Number JP17H01574 (TY). In addition, this study was supported by the Collaborative Research Project of Brain Research Institute, Niigata University under Grant Numbers 2018-2809 (YK) and RIKEN Epigenetics Presidential Fund (100214-201801063606-340120) (TY).
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http://dx.doi.org/10.1016/j.ebiom.2019.05.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642071PMC
July 2019

GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABA receptor trafficking and social behavior.

Sci Adv 2019 04 10;5(4):eaau8237. Epub 2019 Apr 10.

Laboratory for Protein Conformation Diseases, RIKEN Center for Brain Science, Wako, Saitama 351-0198, Japan.

Dysfunctional mTOR signaling is associated with the pathogenesis of neurodevelopmental and neuropsychiatric disorders. However, it is unclear what molecular mechanisms and pathogenic mediators are involved and whether mTOR-regulated autophagy continues to be crucial beyond neurodevelopment. Here, we selectively deleted in forebrain GABAergic interneurons in adolescent mice and unexpectedly found that these mice showed a set of behavioral deficits similar to deletion in forebrain excitatory neurons. By unbiased quantitative proteomic analysis, we identified γ-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2) to differentially form high-molecular weight species in autophagy-deficient brains. Further functional analyses revealed a novel pathogenic mechanism involving the p62-dependent sequestration of GABARAP family proteins, leading to the reduction of surface GABA receptor levels. Our work demonstrates a novel physiological role for autophagy in regulating GABA signaling beyond postnatal neurodevelopment, providing a potential mechanism for the reduced inhibitory inputs observed in neurodevelopmental and neuropsychiatric disorders with mTOR hyperactivation.
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http://dx.doi.org/10.1126/sciadv.aau8237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457945PMC
April 2019

Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation.

Proc Natl Acad Sci U S A 2019 04 19;116(14):7083-7088. Epub 2019 Mar 19.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 260-8670 Chiba, Japan;

Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or ) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.
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http://dx.doi.org/10.1073/pnas.1819234116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452650PMC
April 2019