Acetylserotonin O-Methyltransferase

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 159 Experts worldwide ranked by ideXlab platform

Jonas Melke - One of the best experts on this subject based on the ideXlab platform.

  • Mutation screening of melatonin-related genes in patients with autism spectrum disorders.
    BMC Medical Genomics, 2010
    Co-Authors: Lina Jonsson, Elin Ljunggren, Anna Bremer, Christin T. Pedersen, Mikael Landén, Kent Thuresson, Maibritt Giacobini, Jonas Melke
    Abstract:

    Background One consistent finding in autism spectrum disorders (ASD) is a decreased level of the pineal gland hormone melatonin and it has recently been demonstrated that this decrease to a large extent is due to low activity of the Acetylserotonin O-Methyltransferase (ASMT), the last enzyme in the melatonin synthesis pathway. Moreover, mutations in the ASMT gene have been identified, including a splice site mutation, that were associated with low ASMT activity and melatonin secretion, suggesting that the low ASMT activity observed in autism is, at least partly, due to variation within the ASMT gene.

  • Mutation screening of melatonin-related genes in patients with autism spectrum disorders
    BMC Medical Genomics, 2010
    Co-Authors: Lina Jonsson, Elin Ljunggren, Anna Bremer, Mikael Landén, Kent Thuresson, Maibritt Giacobini, Christin Pedersen, Jonas Melke
    Abstract:

    Background One consistent finding in autism spectrum disorders (ASD) is a decreased level of the pineal gland hormone melatonin and it has recently been demonstrated that this decrease to a large extent is due to low activity of the Acetylserotonin O-Methyltransferase (ASMT), the last enzyme in the melatonin synthesis pathway. Moreover, mutations in the ASMT gene have been identified, including a splice site mutation, that were associated with low ASMT activity and melatonin secretion, suggesting that the low ASMT activity observed in autism is, at least partly, due to variation within the ASMT gene. Methods In the present study, we have investigated all the genes involved in the melatonin pathway by mutation screening of AA-NAT (arylalkylamine N-acetyltransferase), ASMT, MTNR1A, MTNR1B (melatonin receptor 1A and 1B) and GPR50 (G protein-coupled receptor 50), encoding both synthesis enzymes and the three main receptors of melatonin, in 109 patients with autism spectrum disorders (ASD). A cohort of 188 subjects from the general population was used as a comparison group and was genotyped for the variants identified in the patient sample. Results Several rare variants were identified in patients with ASD, including the previously reported splice site mutation in ASMT (IVS5+2T>C). Of the variants affecting protein sequence, only the V124I in the MTNR1B gene was absent in our comparison group. However, mutations were found in upstream regulatory regions in three of the genes investigated, ASMT, MTNR1A , and MTNR1B . Conclusions Our report of another ASD patient carrying the splice site mutation IVS5+2T>C, in ASMT further supports an involvement of this gene in autism. Moreover, our results also suggest that other melatonin related genes might be interesting candidates for further investigation in the search for genes involved in autism spectrum disorders and related neurobehavioral phenotypes. However, further studies of the novel variants identified in this study are warranted to shed light on their potential role in the pathophysiology of these disorders.

Kyoungwhan Back - One of the best experts on this subject based on the ideXlab platform.

  • Rice N-Acetylserotonin deacetylase regulates melatonin levels in transgenic rice
    Melatonin Research, 2020
    Co-Authors: Ok Jin Hwang, Kyoungwhan Back
    Abstract:

    A reverse melatonin biosynthetic pathway was recently discovered in plants, by which N-Acetylserotonin (NAS) is converted into serotonin by N-Acetylserotonin deacetylase (ASDAC) rather than into melatonin by N-Acetylserotonin O-Methyltransferase (ASMT). In this study, we generated transgenic rice plants in which ASDAC was either suppressed or overexpressed to determine whether ASDAC is functionally involved in melatonin biosynthesis. ASDAC-suppressed rice showed increased levels of NAS, 5-methoxytryptamine (5-MT), and melatonin, whereas ASDAC-overexpressed rice exhibited less melatonin synthesis than observed in the wild type. This finding is strong evidence of the role of ASDAC in melatonin biosynthesis in rice. The increased levels of 5-MT, which is produced either by ASDAC from melatonin or by serotonin O-Methyltransferase (SOMT) from serotonin in ASDAC-suppressed rice, was ascribed to enhanced SOMT enzyme activity rather than increased transcripts, such as ASMT or caffeic acid O-Methyltransferase (COMT) encoding SOMT activity.

  • Melatonin production in Escherichia coli by dual expression of serotonin N-acetyltransferase and caffeic acid O-Methyltransferase
    Applied Microbiology and Biotechnology, 2016
    Co-Authors: Yeong Byeon, Kyoungwhan Back
    Abstract:

    Melatonin is a well-known bioactive molecule produced in animals and plants and a well-studied natural compound. Two enzymatic steps are required for the biosynthesis of melatonin from serotonin. First, serotonin N -acetyltransferase (SNAT) catalyzes serotonin to N -Acetylserotonin (NAS) followed by the action of N -Acetylserotonin O -methyltransferase (ASMT), resulting in the synthesis of O -methylated NAS, also known as melatonin. Attempts to document melatonin production in Escherichia coli have been unsuccessful to date due to either low enzyme activity or inactive ASMT expression. Here, we employed caffeic acid O -methyltransferase (COMT) instead of ASMT, as COMT is a multifunctional enzyme that has ASMT activity as well. Among several combinations of dual expression cassettes, recombinant E. coli that expressed sheep SNAT with rice COMT produced a high quantity of melatonin, which was measured in a culture medium (1.46 mg/L in response to 1 m m serotonin). This level was several orders of magnitude higher than that produced in transgenic rice and tomato overexpressing sheep SNAT and ASMT , respectively. This heterologous expression system can be widely employed to screen various putative SNAT or ASMT genes from animals and plants as well as to overproduce melatonin in various useful microorganisms.

  • On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species.
    Journal of Pineal Research, 2016
    Co-Authors: Rüdiger Hardeland, Kyoungwhan Back, Lucien C. Manchester, Moisés Alejandro Alatorre-jiménez, Russel J. Reiter
    Abstract:

    Melatonin is a phylogenetically ancient molecule. It is ubiquitously present in almost all organisms from primitive photosynthetic bacteria to humans. Its original primary function is presumable to be that of an antioxidant with other functions of this molecule having been acquired during evolution. The synthetic pathway of melatonin in vertebrates has been extensively studied. It is common knowledge that serotonin is acetylated to form N-Acetylserotonin by arylalkylamine N-acetyltransferase (AANAT) or arylamine N-acetyltransferase (SNAT or NAT) and N-Acetylserotonin is, subsequently, methylated to melatonin by N-Acetylserotonin O-Methyltransferase (ASMT; also known as hydroxyindole-O-Methyltransferase, HIOMT). This is referred to as a classic melatonin synthetic pathway. Based on new evidence, we feel that this classic melatonin pathway is not generally the prevailing route of melatonin production. An alternate pathway is known to exist, in which serotonin is first O-methylated to 5-methoxytryptamine (5-MT) and, thereafter, 5-MT is N-acetylated to melatonin. Here, we hypothesize that the alternate melatonin synthetic pathway may be more important in certain organisms and under certain conditions. Evidence strongly supports that this alternate pathway prevails in some plants, bacteria, and, perhaps, yeast and may also occur in animals.

  • Cloning and functional characterization of the Arabidopsis N-Acetylserotonin O-Methyltransferase responsible for melatonin synthesis.
    Journal of Pineal Research, 2015
    Co-Authors: Yeong Byeon, Kyoungwhan Back
    Abstract:

    The N-Acetylserotonin O-Methyltransferase (ASMT) gene encodes the enzyme that catalyzes the conversion of N-Acetylserotonin to melatonin as the last step in melatonin biosynthesis. The first plant ASMT gene to be cloned was from rice. An orthologous gene encoding a protein with ASMT activity and only 39.7% amino acid sequence identity to the rice ASMT protein was recently isolated from apple (Malus zumi). The low homology of the apple ASMT sequence prompted us to screen the Arabidopsis genome for a homologous ASMT gene. The At4g35160 gene exhibited the highest sequence identity (31%) to the rice ASMT gene, followed by the At1g76790 gene with 29% sequence identity. We purified recombinant proteins expressed from the two Arabidopsis genes. The At4g35160 recombinant protein exhibited ASMT enzyme activity, but the At1g76790 recombinant protein did not; thus, we designated At4g35160 as an Arabidopsis thaliana ASMT (AtASMT) gene. The AtASMT protein catalyzed the conversion of N-Acetylserotonin to melatonin and serotonin to 5-methoxytryptamine with Vmax values of 0.11 and 0.29 pkat/mg protein, respectively. However, AtASMT exhibited no caffeic acid O-Methyltransferase activity, suggesting that its function was highly specific to melatonin synthesis. AtASMT transcripts were induced by cadmium treatment in Arabidopsis followed by increased melatonin synthesis. Similar to other ASMT proteins, AtASMT was localized in the cytoplasm and its ectopic overexpression in rice resulted in increased ASMT enzyme activity and melatonin production, indicating the involvement of AtASMT in melatonin synthesis.

  • Predominance of 2-hydroxymelatonin over melatonin in plants.
    Journal of Pineal Research, 2015
    Co-Authors: Yeong Byeon, Russel J. Reiter, Kyoungwhan Back
    Abstract:

    : The cloning of the gene encoding melatonin 2-hydroxylase (M2H), which is responsible for the synthesis of 2-hydroxymelatonin, has expanded the study of melatonin metabolism in plants. Kinetic analysis of M2H enzymatic activity demonstrated that the catalytic efficiency of M2H is much higher than those of other melatonin biosynthetic enzymes such as serotonin N-acetyltransferase (SNAT) and N-Acetylserotonin O-Methyltransferase (ASMT), suggesting that melatonin metabolism is rapid in plants. To test this prediction, we selected 24 plant species belonging to 16 families and quantified the levels of melatonin and 2-hydroxymelatonin using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The melatonin levels in most of the species were

Lina Jonsson - One of the best experts on this subject based on the ideXlab platform.

  • Genetic studies of autism and autistic-like traits
    2015
    Co-Authors: Lina Jonsson
    Abstract:

    Autism spectrum disorder (ASD) is characterized by impairment in social interaction, language impairment and repetitive behavior with varying degrees of severity. ASD represents the lower end on a continuously distributed measure of autistic-like traits (ALTs). Although a strong genetic component has repeatedly been identified in ASD, the genetic cause of ASD is still unknown for the majority of ASD cases. One of the main interests in this thesis is the neurobiology of melatonin, this interest is based on findings indicating lower levels of melatonin in children with ASD. In our investigations of rare mutations in melatonin related genes in subjects with ASD, we identified a previously reported mutation that has been shown to decrease the activity of one of the enzymes involved in the melatonin synthesis: the Acetylserotonin O-Methyltransferase (ASMT) (paper I). In the analysis of five common variations in the ASMT gene in relation to ALTs in the general population we found association between a single nucleotide polymorphism and social interaction impairment in girls (paper II). To broaden the analysis of genetic influences on ALTs, we have performed association analyses between ALTs in the general population and common variation in genes previously found to be associated with ASD (RELN, CNTNAP2, SHANK3 and CDH9/10 region) (paper III). Although these regions have previously been suggested to be strong ASD candidate regions, our results do not suggest a major influence of the investigated common variations on ALTs. In the final paper, rare inherited genetic variations were investigated in a large family with autism and language disorders. In this study, we used several techniques, including whole exome sequencing and copy number variation analysis (paper IV). In the family, several rare genetic variations which may partly explain the genetic etiology for autism in this family were identified. We performed functional analyses for a mutation identified in the CYP11A1 gene, indicating a gain of function mutation. The CYP11A1 gene encodes the first enzyme in the steroid hormone biosynthesis, thus our results may be in line with previous findings that have shown an elevated prenatal steroidogenic activity in ASD. In conclusion, we have identified both common and rare genetic variation that may increase the genetic susceptibility for ASD. Our analyses have highlighted the importance of taking both rare and common genetic susceptibility factors, as well as different symptoms of the disorders, into account when elucidating the complex inheritance of ASDs.

  • Mutation screening of melatonin-related genes in patients with autism spectrum disorders.
    BMC Medical Genomics, 2010
    Co-Authors: Lina Jonsson, Elin Ljunggren, Anna Bremer, Christin T. Pedersen, Mikael Landén, Kent Thuresson, Maibritt Giacobini, Jonas Melke
    Abstract:

    Background One consistent finding in autism spectrum disorders (ASD) is a decreased level of the pineal gland hormone melatonin and it has recently been demonstrated that this decrease to a large extent is due to low activity of the Acetylserotonin O-Methyltransferase (ASMT), the last enzyme in the melatonin synthesis pathway. Moreover, mutations in the ASMT gene have been identified, including a splice site mutation, that were associated with low ASMT activity and melatonin secretion, suggesting that the low ASMT activity observed in autism is, at least partly, due to variation within the ASMT gene.

  • Mutation screening of melatonin-related genes in patients with autism spectrum disorders
    BMC Medical Genomics, 2010
    Co-Authors: Lina Jonsson, Elin Ljunggren, Anna Bremer, Mikael Landén, Kent Thuresson, Maibritt Giacobini, Christin Pedersen, Jonas Melke
    Abstract:

    Background One consistent finding in autism spectrum disorders (ASD) is a decreased level of the pineal gland hormone melatonin and it has recently been demonstrated that this decrease to a large extent is due to low activity of the Acetylserotonin O-Methyltransferase (ASMT), the last enzyme in the melatonin synthesis pathway. Moreover, mutations in the ASMT gene have been identified, including a splice site mutation, that were associated with low ASMT activity and melatonin secretion, suggesting that the low ASMT activity observed in autism is, at least partly, due to variation within the ASMT gene. Methods In the present study, we have investigated all the genes involved in the melatonin pathway by mutation screening of AA-NAT (arylalkylamine N-acetyltransferase), ASMT, MTNR1A, MTNR1B (melatonin receptor 1A and 1B) and GPR50 (G protein-coupled receptor 50), encoding both synthesis enzymes and the three main receptors of melatonin, in 109 patients with autism spectrum disorders (ASD). A cohort of 188 subjects from the general population was used as a comparison group and was genotyped for the variants identified in the patient sample. Results Several rare variants were identified in patients with ASD, including the previously reported splice site mutation in ASMT (IVS5+2T>C). Of the variants affecting protein sequence, only the V124I in the MTNR1B gene was absent in our comparison group. However, mutations were found in upstream regulatory regions in three of the genes investigated, ASMT, MTNR1A , and MTNR1B . Conclusions Our report of another ASD patient carrying the splice site mutation IVS5+2T>C, in ASMT further supports an involvement of this gene in autism. Moreover, our results also suggest that other melatonin related genes might be interesting candidates for further investigation in the search for genes involved in autism spectrum disorders and related neurobehavioral phenotypes. However, further studies of the novel variants identified in this study are warranted to shed light on their potential role in the pathophysiology of these disorders.

William Davies - One of the best experts on this subject based on the ideXlab platform.

  • Altered brain gene expression but not steroid biochemistry in a genetic mouse model of neurodevelopmental disorder
    Molecular Autism, 2014
    Co-Authors: Simon Trent, Obah A. Ojarikre, William Davies
    Abstract:

    Background The 39,X^Y*O mouse, which lacks the orthologues of the ADHD and autism candidate genes STS (steroid sulphatase) and ASMT (Acetylserotonin O-Methyltransferase), exhibits behavioural phenotypes relevant to developmental disorders. The neurobiology underlying these phenotypes is unclear, although there is evidence for serotonergic abnormalities in the striatum and hippocampus. Methods Using microarray and quantitative gene expression analyses, and gas chromatography–mass spectrometry, we compared brain gene expression and steroid biochemistry in wildtype (40,XY) and 39,X^Y*O adult mice to identify non-obvious genetic and endocrine candidates for between-group differences in behaviour and neurochemistry. We also tested whether acute STS inhibition by COUMATE in wildtype (40,XY) adult male mice recapitulated any significant gene expression or biochemical findings from the genetic comparison. Data were analysed by unpaired t -test or Mann Whitney U -test depending on normality, with a single factor of KARYOTYPE. Results Microarray analysis indicated seven robust gene expression differences between the two groups ( Vmn2r86 , Sfi1 , Pisd-ps1 , Tagap1 , C1qc , Metap1d , Erdr1 ); Erdr1 and C1qc expression was significantly reduced in the 39,X^Y*O striatum and hippocampus, whilst the expression of Dhcr7 (encoding 7-dehydrocholesterol reductase, a modulator of serotonin system development), was only reduced in the 39,X^Y*O hippocampus. None of the confirmed gene expression changes could be recapitulated by COUMATE administration. We detected ten free, and two sulphated steroids in 40,XY and 39,X^Y*O brain; surprisingly, the concentrations of all of these were equivalent between groups. Conclusions Our data demonstrate that the mutation in 39,X^Y*O mice: i) directly disrupts expression of the adjacent Erdr1 gene, ii) induces a remarkably limited suite of downstream gene expression changes developmentally, with several of relevance to associated neurobehavioural phenotypes and iii) does not elicit large changes in brain steroid biochemistry. It is possible that individuals with STS / ASMT deficiency exhibit a similarly specific pattern of gene expression changes to the 39,X^Y*O mouse, and that these contribute towards their abnormal neurobiology. Future work may focus on whether complement pathway function, mitochondrial metabolism and cholesterol biosynthesis pathways are perturbed in such subjects.

  • Altered brain gene expression but not steroid biochemistry in a genetic mouse model of neurodevelopmental disorder
    Molecular Autism, 2014
    Co-Authors: Simon Trent, Obah A. Ojarikre, William Davies
    Abstract:

    Background: The 39,X Y* O mouse, which lacks the orthologues of the ADHD and autism candidate genes STS (steroid sulphatase) and ASMT (Acetylserotonin O-Methyltransferase), exhibits behavioural phenotypes relevant to developmental disorders. The neurobiology underlying these phenotypes is unclear, although there is evidence for serotonergic abnormalities in the striatum and hippocampus. Methods: Using microarray and quantitative gene expression analyses, and gas chromatography–mass spectrometry, we compared brain gene expression and steroid biochemistry in wildtype (40,XY) and 39,X Y* O adult mice to identify non-obvious genetic and endocrine candidates for between-group differences in behaviour and neurochemistry. We also tested whether acute STS inhibition by COUMATE in wildtype (40,XY) adult male mice recapitulated any significant gene expression or biochemical findings from the genetic comparison. Data were analysed by unpaired t-test or Mann Whitney U-test depending on normality, with a single factor of KARYOTYPE. Results: Microarray analysis indicated seven robust gene expression differences between the two groups (Vmn2r86, Sfi1, Pisd-ps1, Tagap1, C1qc, Metap1d, Erdr1); Erdr1 and C1qc expression was significantly reduced in the 39,X Y* O striatum and hippocampus, whilst the expression of Dhcr7 (encoding 7-dehydrocholesterol reductase, a modulator of serotonin system development), was only reduced in the 39,X Y* O hippocampus. None of the confirmed gene expression changes could be recapitulated by COUMATE administration. We detected ten free, and two sulphated steroids in 40,XY and 39,X Y* O brain; surprisingly, the concentrations of all of these were equivalent between groups. Conclusions: Our data demonstrate that the mutation in 39,X Y* O mice: i) directly disrupts expression of the adjacent Erdr1 gene, ii) induces a remarkably limited suite of downstream gene expression changes developmentally, with several of relevance to associated neurobehavioural phenotypes and iii) does not elicit large changes in brain steroid biochemistry. It is possible that individuals with STS/ASMT deficiency exhibit a similarly

  • Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder.
    Psychoneuroendocrinology, 2012
    Co-Authors: Simon Trent, Rachel Dean, Bonnie Veit, Tommaso Cassano, Gaurav Bedse, Obah A. Ojarikre, Trevor Humby, William Davies
    Abstract:

    Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,XY*O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,XY*O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding Acetylserotonin-O-Methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,XY*O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a ‘foraging’ task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or ‘ability to wait’, it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,XY*O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,XY*O model.

Simon Trent - One of the best experts on this subject based on the ideXlab platform.

  • Altered brain gene expression but not steroid biochemistry in a genetic mouse model of neurodevelopmental disorder
    Molecular Autism, 2014
    Co-Authors: Simon Trent, Obah A. Ojarikre, William Davies
    Abstract:

    Background The 39,X^Y*O mouse, which lacks the orthologues of the ADHD and autism candidate genes STS (steroid sulphatase) and ASMT (Acetylserotonin O-Methyltransferase), exhibits behavioural phenotypes relevant to developmental disorders. The neurobiology underlying these phenotypes is unclear, although there is evidence for serotonergic abnormalities in the striatum and hippocampus. Methods Using microarray and quantitative gene expression analyses, and gas chromatography–mass spectrometry, we compared brain gene expression and steroid biochemistry in wildtype (40,XY) and 39,X^Y*O adult mice to identify non-obvious genetic and endocrine candidates for between-group differences in behaviour and neurochemistry. We also tested whether acute STS inhibition by COUMATE in wildtype (40,XY) adult male mice recapitulated any significant gene expression or biochemical findings from the genetic comparison. Data were analysed by unpaired t -test or Mann Whitney U -test depending on normality, with a single factor of KARYOTYPE. Results Microarray analysis indicated seven robust gene expression differences between the two groups ( Vmn2r86 , Sfi1 , Pisd-ps1 , Tagap1 , C1qc , Metap1d , Erdr1 ); Erdr1 and C1qc expression was significantly reduced in the 39,X^Y*O striatum and hippocampus, whilst the expression of Dhcr7 (encoding 7-dehydrocholesterol reductase, a modulator of serotonin system development), was only reduced in the 39,X^Y*O hippocampus. None of the confirmed gene expression changes could be recapitulated by COUMATE administration. We detected ten free, and two sulphated steroids in 40,XY and 39,X^Y*O brain; surprisingly, the concentrations of all of these were equivalent between groups. Conclusions Our data demonstrate that the mutation in 39,X^Y*O mice: i) directly disrupts expression of the adjacent Erdr1 gene, ii) induces a remarkably limited suite of downstream gene expression changes developmentally, with several of relevance to associated neurobehavioural phenotypes and iii) does not elicit large changes in brain steroid biochemistry. It is possible that individuals with STS / ASMT deficiency exhibit a similarly specific pattern of gene expression changes to the 39,X^Y*O mouse, and that these contribute towards their abnormal neurobiology. Future work may focus on whether complement pathway function, mitochondrial metabolism and cholesterol biosynthesis pathways are perturbed in such subjects.

  • Altered brain gene expression but not steroid biochemistry in a genetic mouse model of neurodevelopmental disorder
    Molecular Autism, 2014
    Co-Authors: Simon Trent, Obah A. Ojarikre, William Davies
    Abstract:

    Background: The 39,X Y* O mouse, which lacks the orthologues of the ADHD and autism candidate genes STS (steroid sulphatase) and ASMT (Acetylserotonin O-Methyltransferase), exhibits behavioural phenotypes relevant to developmental disorders. The neurobiology underlying these phenotypes is unclear, although there is evidence for serotonergic abnormalities in the striatum and hippocampus. Methods: Using microarray and quantitative gene expression analyses, and gas chromatography–mass spectrometry, we compared brain gene expression and steroid biochemistry in wildtype (40,XY) and 39,X Y* O adult mice to identify non-obvious genetic and endocrine candidates for between-group differences in behaviour and neurochemistry. We also tested whether acute STS inhibition by COUMATE in wildtype (40,XY) adult male mice recapitulated any significant gene expression or biochemical findings from the genetic comparison. Data were analysed by unpaired t-test or Mann Whitney U-test depending on normality, with a single factor of KARYOTYPE. Results: Microarray analysis indicated seven robust gene expression differences between the two groups (Vmn2r86, Sfi1, Pisd-ps1, Tagap1, C1qc, Metap1d, Erdr1); Erdr1 and C1qc expression was significantly reduced in the 39,X Y* O striatum and hippocampus, whilst the expression of Dhcr7 (encoding 7-dehydrocholesterol reductase, a modulator of serotonin system development), was only reduced in the 39,X Y* O hippocampus. None of the confirmed gene expression changes could be recapitulated by COUMATE administration. We detected ten free, and two sulphated steroids in 40,XY and 39,X Y* O brain; surprisingly, the concentrations of all of these were equivalent between groups. Conclusions: Our data demonstrate that the mutation in 39,X Y* O mice: i) directly disrupts expression of the adjacent Erdr1 gene, ii) induces a remarkably limited suite of downstream gene expression changes developmentally, with several of relevance to associated neurobehavioural phenotypes and iii) does not elicit large changes in brain steroid biochemistry. It is possible that individuals with STS/ASMT deficiency exhibit a similarly

  • Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder.
    Psychoneuroendocrinology, 2012
    Co-Authors: Simon Trent, Rachel Dean, Bonnie Veit, Tommaso Cassano, Gaurav Bedse, Obah A. Ojarikre, Trevor Humby, William Davies
    Abstract:

    Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,XY*O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,XY*O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding Acetylserotonin-O-Methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,XY*O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a ‘foraging’ task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or ‘ability to wait’, it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,XY*O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,XY*O model.