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Valladão SC, França AP, Pandolfo P, Dos Santos-Rodrigues A. Adenosinergic system and nucleoside transporters in attention deficit hyperactivity disorder: Current findings. Neurosci Biobehav Rev 2024; 164:105771. [PMID: 38880409 DOI: 10.1016/j.neubiorev.2024.105771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/18/2024]
Abstract
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heterogeneity that can affect individuals of any age. It is characterized by three main symptoms: inattention, hyperactivity, and impulsivity. These neurobehavioral alterations and neurochemical and pharmacological findings are mainly attributed to unbalanced catecholaminergic signaling, especially involving dopaminergic pathways within prefrontal and striatal areas. Dopamine receptors and transporters are not solely implicated in this imbalance, as evidence indicates that the dopaminergic signaling is modulated by adenosine activity. To this extent, alterations in adenosinergic signaling are probably involved in ADHD. Here, we review the current knowledge about adenosine's role in the modulation of chemical, behavioral and cognitive parameters of ADHD, especially regarding dopaminergic signaling. Current literature usually links adenosine receptors signaling to the dopaminergic imbalance found in ADHD, but there is evidence that equilibrative nucleoside transporters (ENTs) could also be implicated as players in dopaminergic signaling alterations seen in ADHD, since their involvement in other neurobehavioral impairments.
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Affiliation(s)
- Sofia Corrêa Valladão
- Graduate Program of Neurosciences and Department of Neurobiology, Institute of Biology, Universidade Federal Fluminense, Niterói, Brazil; Graduate Program of Physiology and Pharmacology, Biomedical Institute, Universidade Federal Fluminense, Niterói, Brazil.
| | - Angela Patricia França
- Graduate Program in Neuroscience, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Brazil; Graduate Program in Medical Sciences, Centre of Health Sciences, Federal University of Santa Catarina, Brazil.
| | - Pablo Pandolfo
- Graduate Program of Neurosciences and Department of Neurobiology, Institute of Biology, Universidade Federal Fluminense, Niterói, Brazil; Graduate Program of Physiology and Pharmacology, Biomedical Institute, Universidade Federal Fluminense, Niterói, Brazil.
| | - Alexandre Dos Santos-Rodrigues
- Graduate Program of Neurosciences and Department of Neurobiology, Institute of Biology, Universidade Federal Fluminense, Niterói, Brazil.
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Wren GH, Flanagan J, Underwood JFG, Thompson AR, Humby T, Davies W. Memory, mood and associated neuroanatomy in individuals with steroid sulphatase deficiency (X-linked ichthyosis). GENES, BRAIN, AND BEHAVIOR 2024; 23:e12893. [PMID: 38704684 PMCID: PMC11070068 DOI: 10.1111/gbb.12893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/08/2024] [Accepted: 03/04/2024] [Indexed: 05/07/2024]
Abstract
Steroid sulphatase (STS) cleaves sulphate groups from steroid hormones, and steroid (sulphate) levels correlate with mood and age-related cognitive decline. In animals, STS inhibition or deletion of the associated gene, enhances memory/neuroprotection and alters hippocampal neurochemistry. Little is known about the consequences of constitutive STS deficiency on memory-related processes in humans. We investigated self-reported memory performance (Multifactorial Memory Questionnaire), word-picture recall and recent mood (Kessler Psychological Distress Scale, K10) in adult males with STS deficiency diagnosed with the dermatological condition X-linked ichthyosis (XLI; n = 41) and in adult female carriers of XLI-associated genetic variants (n = 79); we compared results to those obtained from matched control subjects [diagnosed with ichthyosis vulgaris (IV, n = 98) or recruited from the general population (n = 250)]. Using the UK Biobank, we compared mood/memory-related neuroanatomy in carriers of genetic deletions encompassing STS (n = 28) and non-carriers (n = 34,522). We found poorer word-picture recall and lower perceived memory abilities in males with XLI and female carriers compared with control groups. XLI-associated variant carriers and individuals with IV reported more adverse mood symptoms, reduced memory contentment and greater use of memory aids, compared with general population controls. Mood and memory findings appeared largely independent. Neuroanatomical analysis only indicated a nominally-significantly larger molecular layer in the right hippocampal body of deletion carriers relative to non-carriers. In humans, constitutive STS deficiency appears associated with mood-independent impairments in memory but not with large effects on underlying brain structure; the mediating psychobiological mechanisms might be explored further in individuals with XLI and in new mammalian models lacking STS developmentally.
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Affiliation(s)
| | - Jessica Flanagan
- Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and GenomicsSchool of Medicine, Cardiff UniversityCardiffUK
| | - Jack F. G. Underwood
- Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and GenomicsSchool of Medicine, Cardiff UniversityCardiffUK
- Neuroscience and Mental Health Innovation InstituteCardiff UniversityCardiffUK
| | - Andrew R. Thompson
- School of PsychologyCardiff UniversityCardiffUK
- South Wales Clinical Psychology Doctoral ProgrammeCardiff and Vale University Health BoardCardiffUK
| | | | - William Davies
- School of PsychologyCardiff UniversityCardiffUK
- Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and GenomicsSchool of Medicine, Cardiff UniversityCardiffUK
- Neuroscience and Mental Health Innovation InstituteCardiff UniversityCardiffUK
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Kim D, Yadav D, Song M. An updated review on animal models to study attention-deficit hyperactivity disorder. Transl Psychiatry 2024; 14:187. [PMID: 38605002 PMCID: PMC11009407 DOI: 10.1038/s41398-024-02893-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 03/18/2024] [Accepted: 03/25/2024] [Indexed: 04/13/2024] Open
Abstract
Attention-deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder affecting both children and adolescents. Individuals with ADHD experience heterogeneous problems, such as difficulty in attention, behavioral hyperactivity, and impulsivity. Recent studies have shown that complex genetic factors play a role in attention-deficit hyperactivity disorders. Animal models with clear hereditary traits are crucial for studying the molecular, biological, and brain circuit mechanisms underlying ADHD. Owing to their well-managed genetic origins and the relative simplicity with which the function of neuronal circuits is clearly established, models of mice can help learn the mechanisms involved in ADHD. Therefore, in this review, we highlighting the important genetic animal models that can be used to study ADHD.
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Affiliation(s)
- Daegeon Kim
- Department of Life Science, Yeungnam University, Gyeongsan-si, South Korea
| | - Dhananjay Yadav
- Department of Life Science, Yeungnam University, Gyeongsan-si, South Korea
| | - Minseok Song
- Department of Life Science, Yeungnam University, Gyeongsan-si, South Korea.
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Wang J, Feng Y, Liu B, Xie W. Estrogen sulfotransferase and sulfatase in steroid homeostasis, metabolic disease, and cancer. Steroids 2024; 201:109335. [PMID: 37951289 PMCID: PMC10842091 DOI: 10.1016/j.steroids.2023.109335] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/26/2023] [Accepted: 11/06/2023] [Indexed: 11/13/2023]
Abstract
Sulfation and desulfation of steroids are opposing processes that regulate the activation, metabolism, excretion, and storage of steroids, which account for steroid homeostasis. Steroid sulfation and desulfation are catalyzed by cytosolic sulfotransferase and steroid sulfatase, respectively. By modifying and regulating steroids, cytosolic sulfotransferase (SULT) and steroid sulfatase (STS) are also involved in the pathophysiology of steroid-related diseases, such as hormonal dysregulation, metabolic disease, and cancer. The estrogen sulfotransferase (EST, or SULT1E1) is a typical member of the steroid SULTs. This review is aimed to summarize the roles of SULT1E1 and STS in steroid homeostasis and steroid-related diseases.
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Affiliation(s)
- Jingyuan Wang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Ye Feng
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Endocrinology and Metabolic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Brian Liu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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Hu H, Huang Y, Hou R, Xu H, Liu Y, Liao X, Xu J, Jiang L, Wang D. Xp22.31 copy number variations in 87 fetuses: refined genotype-phenotype correlations by prenatal and postnatal follow-up. BMC Med Genomics 2023; 16:69. [PMID: 37013593 PMCID: PMC10069036 DOI: 10.1186/s12920-023-01493-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 03/20/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND Xp22.31 deletion and duplication have been described in various studies, but different laboratories interpret pathogenicity differently. OBJECTIVES Our study aimed to refine the genotype-phenotype associations between Xp22.31 copy number variants in fetuses, with the aim of providing data support to genetic counseling. METHODS We retrospectively analyzed karyotyping and single nucleotide polymorphism array results from 87 fetuses and their family members. Phenotypic data were obtained through follow-up visits. RESULTS The percentage of fetuses carrying the Xp22.31 deletions (9 females, 12 males) was 24.1% (n = 21), while duplications (38 females, 28 males) accounted for 75.9% (n = 66). Here, we noted that the typical region (from 6.4 to 8.1 Mb, hg19) was detected in the highest ratio, either in the fetuses with deletions (76.2%, 16 of 21) or duplications (69.7%, 46 of 66). In female deletion carriers, termination of pregnancy was chosen for two fetuses, and the remaining seven were born without distinct phenotypic abnormalities. In male deletion carriers, termination of pregnancy was chosen for four fetuses, and the remaining eight of them displayed ichthyosis without neurodevelopmental anomalies. In two of these cases, the chromosomal imbalance was inherited from the maternal grandfathers, who also only had ichthyosis phenotypes. Among the 66 duplication carriers, two cases were lost at follow-up, and pregnancy was terminated for eight cases. There were no other clinical findings in the rest of the 56 fetuses, including two with Xp22.31 tetrasomy, for either male or female carriers. CONCLUSION Our observations provide support for genetic counseling in male and female carriers of Xp22.31 copy number variants. Most of them are asymptomatic in male deletion carriers, except for skin findings. Our study is consistent with the view that the Xp22.31 duplication may be a benign variant in both sexes.
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Affiliation(s)
- Huamei Hu
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yulin Huang
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Renke Hou
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Huanhuan Xu
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yalan Liu
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xueqian Liao
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Juchun Xu
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Lupin Jiang
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
| | - Dan Wang
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
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Wren GH, Davies W. X-linked ichthyosis: New insights into a multi-system disorder. SKIN HEALTH AND DISEASE 2022; 2:e179. [PMID: 36479267 PMCID: PMC9720199 DOI: 10.1002/ski2.179] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/09/2022] [Indexed: 11/07/2022]
Abstract
Background X-linked ichthyosis (XLI) is a rare genetic condition almostexclusively affecting males; it is characterised by abnormal desquamation and retentionhyperkeratosis, and presents with polygonal brown scales. Most cases resultfrom genetic deletions within Xp22.31 spanning the STS (steroid sulfatase)gene, with the remaining cases resulting from STS-specific mutations. For manyyears it has been recognised that individuals with XLI are at increased risk ofcryptorchidism and corneal opacities. Methods We discuss emerging evidence that such individuals are alsomore likely to be affected by a range of neurodevelopmental and psychiatrictraits, by cardiac arrhythmias, and by rare fibrotic and bleeding-relatedconditions. We consider candidate mechanisms that may confer elevatedlikelihood of these individual conditions, and propose a novel commonbiological risk pathway. Results Understanding the prevalence, nature and co-occurrence ofcomorbidities associated with XLI is critical for ensuring early identificationof symptoms and for providing the most effective genetic counselling andmultidisciplinary care for affected individuals. Conclusion Future work in males with XLI, and in new preclinical andcellular model systems, should further clarify underlying pathophysiologicalmechanisms amenable to therapeutic intervention.
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Affiliation(s)
| | - William Davies
- School of PsychologyCardiff UniversityCardiffUK
- School of MedicineCardiff UniversityCardiffUK
- Centre for Neuropsychiatric Genetics and GenomicsCardiff UniversityCardiffUK
- Neuroscience and Mental Health Innovation InstituteCardiff UniversityCardiffUK
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Vitku J, Hill M, Kolatorova L, Kubala Havrdova E, Kancheva R. Steroid Sulfation in Neurodegenerative Diseases. Front Mol Biosci 2022; 9:839887. [PMID: 35281259 PMCID: PMC8904904 DOI: 10.3389/fmolb.2022.839887] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/20/2022] [Indexed: 11/13/2022] Open
Abstract
Steroid sulfation and desulfation participates in the regulation of steroid bioactivity, metabolism and transport. The authors focused on sulfation and desulfation balance in three neurodegenerative diseases: Alzheimer´s disease (AD), Parkinson´s disease (PD), and multiple sclerosis (MS). Circulating steroid conjugates dominate their unconjugated counterparts, but unconjugated steroids outweigh their conjugated counterparts in the brain. Apart from the neurosteroid synthesis in the central nervous system (CNS), most brain steroids cross the blood-brain barrier (BBB) from the periphery and then may be further metabolized. Therefore, steroid levels in the periphery partly reflect the situation in the brain. The CNS steroids subsequently influence the neuronal excitability and have neuroprotective, neuroexcitatory, antidepressant and memory enhancing effects. They also exert anti-inflammatory and immunoprotective actions. Like the unconjugated steroids, the sulfated ones modulate various ligand-gated ion channels. Conjugation by sulfotransferases increases steroid water solubility and facilitates steroid transport. Steroid sulfates, having greater half-lives than their unconjugated counterparts, also serve as a steroid stock pool. Sulfotransferases are ubiquitous enzymes providing massive steroid sulfation in adrenal zona reticularis and zona fasciculata.. Steroid sulfatase hydrolyzing the steroid conjugates is exceedingly expressed in placenta but is ubiquitous in low amounts including brain capillaries of BBB which can rapidly hydrolyze the steroid sulfates coming across the BBB from the periphery. Lower dehydroepiandrosterone sulfate (DHEAS) plasma levels and reduced sulfotransferase activity are considered as risk factors in AD patients. The shifted balance towards unconjugated steroids can participate in the pathophysiology of PD and anti-inflammatory effects of DHEAS may counteract the MS.
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Affiliation(s)
- Jana Vitku
- Department of Steroids and Proteofactors, Institute of Endocrinology, Prague, Czechia
- *Correspondence: Jana Vitku,
| | - Martin Hill
- Department of Steroids and Proteofactors, Institute of Endocrinology, Prague, Czechia
| | - Lucie Kolatorova
- Department of Steroids and Proteofactors, Institute of Endocrinology, Prague, Czechia
| | - Eva Kubala Havrdova
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
| | - Radmila Kancheva
- Department of Steroids and Proteofactors, Institute of Endocrinology, Prague, Czechia
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Rahi V, Kumar P. Animal models of attention-deficit hyperactivity disorder (ADHD). Int J Dev Neurosci 2021; 81:107-124. [PMID: 33428802 DOI: 10.1002/jdn.10089] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 12/14/2020] [Accepted: 01/06/2021] [Indexed: 12/15/2022] Open
Abstract
Attention-deficit hyperactivity disorder (ADHD) is a heterogeneous neuropsychiatric disorder characterized by three primary symptoms hyperactivity, attention deficit, and impulsiveness, observed in both children and adults. In childhood, this disorder is more common in boys than in girls, and at least 75% will continue to suffer from the disorder until adulthood. Individuals with ADHD generally have poor academic, occupational, and social functioning resulting from developmentally inappropriate levels of hyperactivity and impulsivity, as well as impaired ability to maintain attention on motivationally relevant tasks. Very few drugs available in clinical practice altogether abolish the symptoms of ADHD, therefore, to find new drugs and target it is essential to understand the neuropathological, neurochemical, and genetic alterations that lead to the progression of ADHD. With this contrast, an animal study is the best approach because animal models provide relatively fast invasive manipulation, rigorous hypothesis testing, as well as it provides a better angle to understand the pathological mechanisms involved in disease progression. Moreover, animal models, especially for ADHD, serve with good predictive validity would allow the assessment and development of new therapeutic interventions, with this aim, the present review collect the various animal models on a single platform so that the research can select an appropriate model to pursue his study.
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Affiliation(s)
- Vikrant Rahi
- Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, India
| | - Puneet Kumar
- Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, India
- Department of Pharmacology, Central University of Punjab, Bathinda, India
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Davies W. The contribution of Xp22.31 gene dosage to Turner and Klinefelter syndromes and sex-biased phenotypes. Eur J Med Genet 2021; 64:104169. [PMID: 33610733 DOI: 10.1016/j.ejmg.2021.104169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/11/2021] [Accepted: 02/16/2021] [Indexed: 11/27/2022]
Abstract
Turner syndrome (TS) is a rare developmental condition in females caused by complete, or partial, loss of the second sex chromosome; it is associated with a number of phenotypes including short stature, ovarian failure and infertility, as well as neurobehavioural and cognitive manifestations. In contrast, Klinefelter syndrome (KS) arises from an excess of X chromosome material in males (typical karyotype is 47,XXY); like TS, KS is associated with infertility and hormonal imbalance, and behavioural/neurocognitive differences from gonadal sex-matched counterparts. Lower dosage of genes that escape X-inactivation may partially explain TS phenotypes, whilst overdosage of these genes may contribute towards KS-related symptoms. Here, I discuss new findings from individuals with deletions or duplications limited to Xp22.31 (a region escaping X-inactivation), and consider the extent to which altered gene dosage within this small interval (and of the steroid sulfatase (STS) gene in particular) may influence the phenotypic profiles of TS and KS. The expression of X-escapees can be higher in female than male tissues; I conclude by considering how lower Xp22.31 gene dosage in males may increase their likelihood of exhibiting particular phenotypes relative to females. Understanding the genetic contribution to specific phenotypes in rare disorders such as TS and KS, and to more common sex-biased phenotypes, will be important for developing more effective, and more personalised, therapeutic approaches.
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Affiliation(s)
- William Davies
- School of Psychology, Cardiff University, Cardiff, UK; Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
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Thippeswamy H, Davies W. A new molecular risk pathway for postpartum mood disorders: clues from steroid sulfatase-deficient individuals. Arch Womens Ment Health 2021; 24:391-401. [PMID: 33219387 PMCID: PMC8116278 DOI: 10.1007/s00737-020-01093-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 11/13/2020] [Indexed: 12/17/2022]
Abstract
Postpartum mood disorders develop shortly after childbirth in a significant proportion of women. These conditions are associated with a range of symptoms including abnormally high or low mood, irritability, cognitive disorganisation, disrupted sleep, hallucinations/delusions, and occasionally suicidal or infanticidal ideation; if not treated promptly, they can substantially impact upon the mother's health, mother-infant bonding, and family dynamics. The biological precipitants of such disorders remain unclear, although large changes in maternal immune and hormonal physiology following childbirth are likely to play a role. Pharmacological therapies for postpartum mood disorders can be effective, but may be associated with side effects, concerns relating to breastfeeding, and teratogenicity risks when used prophylactically. Furthermore, most of the drugs that are used to treat postpartum mood disorders are the same ones that are used to treat mood episodes during non-postpartum periods. A better understanding of the biological factors predisposing to postpartum mood disorders would allow for rational drug development, and the identification of predictive biomarkers to ensure that 'at risk' mothers receive earlier and more effective clinical management. We describe new findings relating to the role of the enzyme steroid sulfatase in maternal postpartum behavioural processes, and discuss how these point to a novel molecular risk pathway underlying postpartum mood disorders. Specifically, we suggest that aberrant steroid hormone-dependent regulation of neuronal calcium influx via extracellular matrix proteins and membrane receptors involved in responding to the cell's microenvironment might be important. Testing of this hypothesis might identify novel therapeutic targets and predictive biomarkers.
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Affiliation(s)
- Harish Thippeswamy
- Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, India
| | - William Davies
- Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. .,School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK. .,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
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Gubb SJA, Brcic L, Underwood JFG, Kendall KM, Caseras X, Kirov G, Davies W. Medical and neurobehavioural phenotypes in male and female carriers of Xp22.31 duplications in the UK Biobank. Hum Mol Genet 2020; 29:2872-2881. [PMID: 32766777 PMCID: PMC7566349 DOI: 10.1093/hmg/ddaa174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/28/2020] [Accepted: 07/28/2020] [Indexed: 12/12/2022] Open
Abstract
Deletions spanning the STS (steroid sulfatase) gene at Xp22.31 are associated with X-linked ichthyosis, corneal opacities, testicular maldescent, cardiac arrhythmia, and higher rates of developmental and mood disorders/traits, possibly related to the smaller volume of some basal ganglia structures. The consequences of duplication of the same genomic region have not been systematically assessed in large or adult samples, although evidence from case reports/series has indicated high rates of developmental phenotypes. We compared multiple measures of physical and mental health, cognition and neuroanatomy in male (n = 414) and female (n = 938) carriers of 0.8-2.5 Mb duplications spanning STS, and non-carrier male (n = 192, 826) and female (n = 227, 235) controls from the UK Biobank (recruited aged 40-69 from the UK general population). Clinical and self-reported diagnoses indicated a higher prevalence of inguinal hernia and mania/bipolar disorder respectively in male duplication carriers, and a higher prevalence of gastro-oesophageal reflux disease and blistering/desquamating skin disorder respectively in female duplication carriers; duplication carriers also exhibited reductions in several depression-related measures, and greater happiness. Cognitive function and academic achievement did not differ between comparison groups. Neuroanatomical analysis suggested greater lateral ventricle and putamen volume in duplication carriers. In conclusion, Xp22.31 duplications appear largely benign, but could slightly increase the likelihood of specific phenotypes (although results were only nominally-significant). In contrast to deletions, duplications might protect against depressive symptoms, possibly via higher STS expression/activity (resulting in elevated endogenous free steroid levels), and through contributing towards an enlarged putamen volume. These results should enable better genetic counselling of individuals with Xp22.31 microduplications.
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Affiliation(s)
- Samuel J A Gubb
- Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom
| | - Lucija Brcic
- School of Psychology, Cardiff University, Cardiff CF10 3AT, United Kingdom
| | - Jack F G Underwood
- Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff CF24 4HQ, United Kingdom
| | - Kimberley M Kendall
- Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom
| | - Xavier Caseras
- Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom
| | - George Kirov
- Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom
| | - William Davies
- Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom
- School of Psychology, Cardiff University, Cardiff CF10 3AT, United Kingdom
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff CF24 4HQ, United Kingdom
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Brcic L, Underwood JF, Kendall KM, Caseras X, Kirov G, Davies W. Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank. J Med Genet 2020; 57:692-698. [PMID: 32139392 PMCID: PMC7525778 DOI: 10.1136/jmedgenet-2019-106676] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/20/2019] [Accepted: 01/23/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND X-linked ichthyosis (XLI) is an uncommon dermatological condition resulting from a deficiency of the enzyme steroid sulfatase (STS), often caused by X-linked deletions spanning STS. Some medical comorbidities have been identified in XLI cases, but small samples of relatively young patients has limited this. STS is highly expressed in subcortical brain structures, and males with XLI and female deletion carriers appear at increased risk of developmental/mood disorders and associated traits; the neurocognitive basis of these findings has not been examined. METHODS Using the UK Biobank resource, comprising participants aged 40-69 years recruited from the general UK population, we compared multiple medical/neurobehavioural phenotypes in males (n=86) and females (n=312) carrying genetic deletions spanning STS (0.8-2.5 Mb) (cases) to male (n=190 577) and female (n=227 862) non-carrier controls. RESULTS We identified an elevated rate of atrial fibrillation/flutter in male deletion carriers (10.5% vs 2.7% in male controls, Benjamini-Hochberg corrected p=0.009), and increased rates of mental distress (p=0.003), irritability (p<0.001) and depressive-anxiety traits (p<0.05) in male deletion carriers relative to male controls completing the Mental Health Questionnaire. While academic attainment was unaffected, male and female deletion carriers exhibited impaired performance on the Fluid Intelligence Test (Cohen's d≤0.05, corrected p<0.1). Neuroanatomical analysis in female deletion carriers indicated reduced right putamen and left nucleus accumbens volumes (Cohen's d≤0.26, corrected p<0.1). CONCLUSION Adult males with XLI disease-causing deletions are apparently at increased risk of cardiac arrhythmias and self-reported mood problems; altered basal ganglia structure may underlie altered function and XLI-associated psychiatric/behavioural phenotypes. These results provide information for genetic counselling of deletion-carrying individuals and reinforce the need for multidisciplinary medical care.
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Affiliation(s)
- Lucija Brcic
- School of Psychology, Cardiff University, Cardiff, UK
| | - Jack Fg Underwood
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
| | - Kimberley M Kendall
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - Xavier Caseras
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - George Kirov
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - William Davies
- School of Psychology, Cardiff University, Cardiff, UK .,MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
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Humby T, Davies W. Brain Gene Expression in a Novel Mouse Model of Postpartum Mood Disorder. Transl Neurosci 2019; 10:168-174. [PMID: 31410299 PMCID: PMC6689211 DOI: 10.1515/tnsci-2019-0030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 06/26/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Steroid sulfatase (STS) cleaves sulfate groups from steroid hormones; its expression/activity increases in late pregnancy and into the postpartum period. STS-deficient human and mouse mothers display elevated psychopathology and abnormal behaviour respectively; in mice, these effects can be partially normalised by antipsychotic (ziprasidone) administration. METHODOLOGY We compared brain gene expression in new mouse mothers administered the STS inhibitor 667-Coumate, or vehicle; significant changes were followed-up with pathway analysis and quantitative polymerase chain reaction (qPCR). Finally, the effects of combined 667-Coumate and ziprasidone administration on expression of the most robustly differentially-expressed genes were examined. RESULTS Surprisingly, no between-group gene expression changes were detected at a False Discovery Rate (FDR)-corrected p<0.1. 1,081 unique expression changes were detected at p<0.05, two top hits were verified by qPCR, and pathway analysis indicated enrichment of genes involved in olfactory transduction. The expression of Stoml3 and Cyp2g1 was unaffected by ziprasidone administration. CONCLUSIONS Postpartum behavioural abnormalities in STS-deficient mothers are likely to be the culmination of many small gene expression changes. Our data are consistent with the idea that olfactory function is key to maternal behaviour in mice, and suggest that aberrant expression of olfactory system genes may underlie abnormal maternal behaviour in STS-deficient women.
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Affiliation(s)
- Trevor Humby
- School of Psychology, Cardiff University, Cardiff CF10 3AT, Cardiff, UK
- Neuroscience and Mental Health Research Institute, Cardiff University, CardiffCF24 4HQ, UK
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, CardiffCF24 4HQ, UK
| | - William Davies
- School of Psychology, Cardiff University, Cardiff CF10 3AT, Cardiff, UK
- Neuroscience and Mental Health Research Institute, Cardiff University, CardiffCF24 4HQ, UK
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, CardiffCF24 4HQ, UK
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Cavenagh A, Chatterjee S, Davies W. Behavioural and psychiatric phenotypes in female carriers of genetic mutations associated with X-linked ichthyosis. PLoS One 2019; 14:e0212330. [PMID: 30768640 PMCID: PMC6377116 DOI: 10.1371/journal.pone.0212330] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 01/31/2019] [Indexed: 12/12/2022] Open
Abstract
X-linked ichthyosis (XLI) is a rare X-linked dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). STS is normally expressed in the brain, and males with XLI exhibit personality differences from males in the general population, and are at increased risk of developmental and mood disorders. As the STS gene escapes X-inactivation, female carriers of XLI-associated genetic mutations have reduced STS expression/activity relative to non-carrier females, and could manifest similar behavioural phenotypes to males with XLI. Additionally, as STS activity normally increases in female tissues towards late pregnancy and into the puerperium, carrier females could theoretically present with increased rates of postpartum psychopathology. Using a worldwide online survey comprising custom-designed demographic questionnaires and multiple validated psychological questionnaires, we collected detailed self-reported information on non-postpartum and postpartum behaviour in confirmed adult (>16yrs) female carriers of genetic mutations associated with XLI (n = 94) for statistical comparison to demographically-matched previously-published normative data from female controls (seven independent studies, 98≤n≤2562), adult males with XLI (n = 58), and to newly-obtained online survey data from a general population sample of mothers from the United Kingdom and United States of America (n = 263). The pattern of results in carrier females relative to controls was remarkably similar to that previously observed in males with XLI, with evidence for increased rates of developmental and mood disorders, and elevated levels of inattention, impulsivity, autism-related traits and general psychological distress. Carrier females exhibited a significantly elevated rate of postpartum mental health conditions (notably mild depression) relative to controls which could not be accounted for by social factors. Our data confirm the psychological profile associated with XLI-associated mutations, and suggest that female carriers may be at increased risk of psychopathology, including in the postpartum period. These findings are relevant to families affected by XLI, to clinicians involved in the care of these families, and to genetic counsellors.
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Affiliation(s)
- Alice Cavenagh
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Sohini Chatterjee
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - William Davies
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
- School of Psychology, Cardiff University, Cardiff, United Kingdom
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
- * E-mail:
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Rodrigo-Nicolás B, Bueno-Martínez E, Martín-Santiago A, Cañueto J, Vicente A, Torrelo A, Noguera-Morel L, Duat-Rodríguez A, Jorge-Finnigan C, Palacios-Álvarez I, García-Hernández J, Sebaratnam D, González-Sarmiento R, Hernández-Martín A. Evidence of the high prevalence of neurological disorders in nonsyndromic X-linked recessive ichthyosis: a retrospective case series. Br J Dermatol 2018; 179:933-939. [DOI: 10.1111/bjd.16826] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2018] [Indexed: 12/11/2022]
Affiliation(s)
| | - E. Bueno-Martínez
- Molecular Medicine Unit-Department of Medicine; IBSAL and IBMCC and University Hospital of Salamanca; CSIC, University of Salamanca; Spain
| | - A. Martín-Santiago
- Department of Dermatology; Hospital Son Espases; Palma de Mallorca Spain
| | - J. Cañueto
- Department of Dermatology; Hospital Universitario de Salamanca; Salamanca Spain
| | - A. Vicente
- Department of Dermatology; Hospital Sant Joan de Deu; Barcelona Spain
| | - A. Torrelo
- Department of Dermatology; Hospital Infantil Niño Jesús; Madrid Spain
| | - L. Noguera-Morel
- Department of Dermatology; Hospital Infantil Niño Jesús; Madrid Spain
| | | | - C. Jorge-Finnigan
- Department of Dermatology; Hospital Infantil Niño Jesús; Madrid Spain
| | | | - J.L. García-Hernández
- Molecular Medicine Unit-Department of Medicine; IBSAL and IBMCC and University Hospital of Salamanca; CSIC, University of Salamanca; Spain
| | - D.F. Sebaratnam
- Department of Dermatology; Hospital Infantil Niño Jesús; Madrid Spain
| | - R. González-Sarmiento
- Molecular Medicine Unit-Department of Medicine; IBSAL and IBMCC and University Hospital of Salamanca; CSIC, University of Salamanca; Spain
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Davies W. SULFATION PATHWAYS: The steroid sulfate axis and its relationship to maternal behaviour and mental health. J Mol Endocrinol 2018; 61:T199-T210. [PMID: 29440314 DOI: 10.1530/jme-17-0219] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 11/16/2017] [Indexed: 12/14/2022]
Abstract
Steroid hormones can exist in functionally dissociable sulfated and non-sulfated (free) forms and can exert profound effects on numerous aspects of mammalian physiology; the ratio of free-to-sulfated steroids is governed by the antagonistic actions of steroid sulfatase (STS) and sulfotransferase (SULT) enzymes. Here, I examine evidence from human and animal model studies, which suggests that STS and its major substrate (dehydroepiandrosterone sulfate, DHEAS) and product (DHEA) can influence brain function, behaviour and mental health, before summarising how the activity of this axis varies throughout mammalian pregnancy and the postpartum period. I then consider how the steroid sulfate axis might impact upon normal maternal behaviour and how its dysfunction might contribute towards risk of postpartum psychiatric illness. Understanding the biological substrates underlying normal and abnormal maternal behaviour will be important for maximising the wellbeing of new mothers and their offspring.
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Affiliation(s)
- William Davies
- School of PsychologyCardiff University, Cardiff, UK
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical NeurosciencesSchool of Medicine, Cardiff University, Cardiff, UK
- Neuroscience and Mental Health Research InstituteCardiff University, Cardiff, UK
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17
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Romano A, Serviddio G, Calcagnini S, Villani R, Giudetti AM, Cassano T, Gaetani S. Linking lipid peroxidation and neuropsychiatric disorders: focus on 4-hydroxy-2-nonenal. Free Radic Biol Med 2017; 111:281-293. [PMID: 28063940 DOI: 10.1016/j.freeradbiomed.2016.12.046] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 12/27/2016] [Accepted: 12/30/2016] [Indexed: 12/25/2022]
Abstract
4-hydroxy-2-nonenal (HNE) is considered to be a strong marker of oxidative stress; the interaction between HNE and cellular proteins leads to the formation of HNE-protein adducts able to alter cellular homeostasis and cause the development of a pathological state. By virtue of its high lipid concentration, oxygen utilization, and the presence of metal ions participating to redox reactions, the brain is highly susceptible to the formation of free radicals and HNE-related compounds. A variety of neuropsychiatric disorders have been associated with elevations of HNE concentration. For example, increased levels of HNE were found in the cortex of bipolar and schizophrenic patients, while HNE plasma concentrations resulted high in patients with major depression. On the same line, high brain concentrations of HNE were found associated with Huntington's inclusions. The incidence of high HNE levels is relevant also in the brain and cerebrospinal fluid of patients suffering from Parkinson's disease. Intriguingly, in this case the increase of HNE was associated with an accumulation of iron in the substantia nigra, a brain region highly affected by the pathology. In the present review we recapitulate the findings supporting the role of HNE in the pathogenesis of different neuropsychiatric disorders to highlight the pathogenic mechanisms ascribed to HNE accumulation. The aim of this review is to offer novel perspectives both for the understanding of etiopathogenetic mechanisms that remain still unclear and for the identification of new useful biological markers. We conclude suggesting that targeting HNE-driven cellular processes may represent a new more efficacious therapeutical intervention.
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Affiliation(s)
- Adele Romano
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy
| | - Gaetano Serviddio
- Department of Medical and Surgical Sciences, University of Foggia, Via Luigi Pinto, c/o Ospedali Riuniti, 71122 Foggia, Italy
| | - Silvio Calcagnini
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy
| | - Rosanna Villani
- Department of Medical and Surgical Sciences, University of Foggia, Via Luigi Pinto, c/o Ospedali Riuniti, 71122 Foggia, Italy
| | - Anna Maria Giudetti
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Centro Ecotekne, sp Lecce-Monteroni 73100 Lecce, Italy
| | - Tommaso Cassano
- Department of Clinical and Experimental Medicine, University of Foggia, Via Luigi Pinto, c/o Ospedali Riuniti, 71122 Foggia, Italy.
| | - Silvana Gaetani
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy
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Zhou RY, Wang JJ, Sun JC, You Y, Ying JN, Han XM. Attention deficit hyperactivity disorder may be a highly inflammation and immune-associated disease (Review). Mol Med Rep 2017; 16:5071-5077. [PMID: 28849096 DOI: 10.3892/mmr.2017.7228] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 06/01/2017] [Indexed: 11/06/2022] Open
Abstract
Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder. Previous research has indicated that genetic factors, family education, environment and dietary habits are associated with ADHD. It has been determined that in China many children with ADHD also have allergic rhinitis or asthma. These children are more susceptible to the common cold or upper respiratory infections compared with normal healthy children. Additionally, the common cold or an upper respiratory infection may lead to disease recurrence or worsen the symptoms in these children. Previous studies have determined that ADHD may have a close association with allergic disease. Based on the clinically observed phenomenon and previous studies, it was hypothesized that ADHD is a high inflammation and immune‑associated disease. Therefore, the authors designed clinical and animal experiments to test this hypothesis in the future. Immune system disorders may be a novel part of the etiology of ADHD. The current report may have implications for future clinical practice.
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Affiliation(s)
- Rong-Yi Zhou
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Jiao-Jiao Wang
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Ji-Chao Sun
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Yue You
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Jing-Nang Ying
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Xin-Min Han
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
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Davies W. Understanding the pathophysiology of postpartum psychosis: Challenges and new approaches. World J Psychiatry 2017; 7:77-88. [PMID: 28713685 PMCID: PMC5491479 DOI: 10.5498/wjp.v7.i2.77] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 01/25/2017] [Accepted: 04/20/2017] [Indexed: 02/05/2023] Open
Abstract
Postpartum psychosis is a severe psychiatric condition which affects 1-2 of every 1000 mothers shortly after childbirth. Whilst there is convincing evidence that the condition is precipitated by a complex combination of biological and environmental factors, as yet the pathophysiological mechanisms remain extremely poorly defined. Here, I critically review approaches that have been, or are being, employed to identify and characterise such mechanisms; I also review a recent animal model approach, and describe a novel biological risk model that it suggests. Clarification of biological risk mechanisms underlying disorder risk should permit the identification of relevant predictive biomarkers which will ensure that “at risk” subjects receive prompt clinical intervention if required.
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de la Peña JB, Dela Peña IJ, Custodio RJ, Botanas CJ, Kim HJ, Cheong JH. Exploring the Validity of Proposed Transgenic Animal Models of Attention-Deficit Hyperactivity Disorder (ADHD). Mol Neurobiol 2017; 55:3739-3754. [PMID: 28534274 DOI: 10.1007/s12035-017-0608-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 05/09/2017] [Indexed: 12/31/2022]
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a common, behavioral, and heterogeneous neurodevelopmental condition characterized by hyperactivity, impulsivity, and inattention. Symptoms of this disorder are managed by treatment with methylphenidate, amphetamine, and/or atomoxetine. The cause of ADHD is unknown, but substantial evidence indicates that this disorder has a significant genetic component. Transgenic animals have become an essential tool in uncovering the genetic factors underlying ADHD. Although they cannot accurately reflect the human condition, they can provide insights into the disorder that cannot be obtained from human studies due to various limitations. An ideal animal model of ADHD must have face (similarity in symptoms), predictive (similarity in response to treatment or medications), and construct (similarity in etiology or underlying pathophysiological mechanism) validity. As the exact etiology of ADHD remains unclear, the construct validity of animal models of ADHD would always be limited. The proposed transgenic animal models of ADHD have substantially increased and diversified over the years. In this paper, we compiled and explored the validity of proposed transgenic animal models of ADHD. Each of the reviewed transgenic animal models has strengths and limitations. Some fulfill most of the validity criteria of an animal model of ADHD and have been extensively used, while there are others that require further validation. Nevertheless, these transgenic animal models of ADHD have provided and will continue to provide valuable insights into the genetic underpinnings of this complex disorder.
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Affiliation(s)
- June Bryan de la Peña
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea
| | - Irene Joy Dela Peña
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea
| | - Raly James Custodio
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea
| | - Chrislean Jun Botanas
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea
| | - Hee Jin Kim
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea
| | - Jae Hoon Cheong
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea.
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Humby T, Cross ES, Messer L, Guerrero S, Davies W. A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis. Psychoneuroendocrinology 2016; 74:363-370. [PMID: 27728876 PMCID: PMC5094271 DOI: 10.1016/j.psyneuen.2016.09.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 09/08/2016] [Accepted: 09/21/2016] [Indexed: 01/04/2023]
Abstract
Postpartum psychosis (PP) is a severe psychiatric disorder affecting a small proportion of new mothers shortly after childbirth. The molecular pathophysiology underlying the disorder is currently poorly understood, and there are no amenable animal models for the condition; maternal deficiency for the enzyme steroid sulfatase has been proposed as a potential risk mechanism. Here we show that inhibition of steroid sulfatase with 667-COUMATE (10mg/kg p.o.) in new mouse mothers results in behavioural abnormalities that can be partially alleviated by the administration of the clinically-efficacious antipsychotic ziprasidone (0.3-1.0mg/kg i.p.). The pattern of behavioural abnormalities in 667-COUMATE-treated mice implicated a genetic substrate at 21-23cM on chromosome 15; of the 17 genes within this chromosomal interval, only one (Nov/Ccn3) was significantly differentially expressed in the brains of vehicle and 667-COUMATE-treated mice. Two additional members of the Ccn family (Ccn2/Ctgf and Ccn4/Wisp1) were also significantly differentially expressed between the two groups, as were three further genes co-expressed with Nov/Ccn3 in brain (Arhgdig) or previously implicated in disorder risk by clinical studies (Adcy8 and Ccl2). The expression of Nov/Ccn3, but not of the other differentially-expressed genes, could be normalised by ziprasidone administration (1.0mg/kg). NOV/CCN3 lies directly under a linkage peak for PP risk at 8q24, and the associated protein possesses numerous characteristics that make it an excellent candidate mediator of PP risk. Our data suggest the 667-COUMATE-treated mouse as a model for PP with some degree of face, construct, and predictive validity, and implicate a novel, and biologically-plausible, molecular risk pathway for PP.
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Affiliation(s)
- Trevor Humby
- School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
| | - Ellen S. Cross
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Lauren Messer
- School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK.
| | - Silvia Guerrero
- University of Barcelona, Gran Via de les Corts Catalanes, 585 08007 Barcelona, Spain.
| | - William Davies
- School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
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Chatterjee S, Humby T, Davies W. Behavioural and Psychiatric Phenotypes in Men and Boys with X-Linked Ichthyosis: Evidence from a Worldwide Online Survey. PLoS One 2016; 11:e0164417. [PMID: 27711218 PMCID: PMC5053497 DOI: 10.1371/journal.pone.0164417] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/23/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND X-linked ichthyosis (XLI) is a rare dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). Preliminary evidence in boys with XLI, and animal model studies, suggests that individuals lacking STS are at increased risk of developmental disorders and associated traits. However, the behavioural profile of children with XLI is poorly-characterised, and the behavioural profile of adults with XLI has not yet been documented at all. MATERIALS AND METHODS Using an online survey, advertised worldwide, we collected detailed self- or parent-reported information on behaviour in adult (n = 58) and younger (≤18yrs, n = 24) males with XLI for comparison to data from their non-affected brothers, and age/gender-matched previously-published normative data. The survey comprised demographic and background information (including any prior clinical diagnoses) and validated questionnaires assaying phenotypes of particular interest (Adult ADHD Self-Report Scale v1.1, Barrett Impulsiveness Scale-11, adult and adolescent Autism Quotient, Kessler Psychological Distress Scales, and Disruptive Behaviour Disorder Rating Scale). RESULTS Individuals with XLI generally exhibited normal sensory function. Boys with XLI were at increased risk of developmental disorder, whilst adults with the condition were at increased risk of both developmental and mood disorders. Both adult and younger XLI groups scored significantly more highly than male general population norms on measures of inattention, impulsivity, autism-related traits, psychological distress and disruptive behavioural traits. CONCLUSIONS These findings indicate that both adult and younger males with XLI exhibit personality profiles that are distinct from those of males within the general population, and suggest that individuals with XLI may be at heightened risk of psychopathology. The data are consistent with the notion that STS is important in neurodevelopment and ongoing brain function, and with previous work suggesting high rates of developmental disorders in boys with XLI. Our results suggest that individuals with XLI may require medical care from multidisciplinary teams, and should help to inform genetic counselling for the condition.
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Affiliation(s)
- Sohini Chatterjee
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Trevor Humby
- School of Psychology, Cardiff University, Cardiff, United Kingdom
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
| | - William Davies
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
- School of Psychology, Cardiff University, Cardiff, United Kingdom
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
- * E-mail:
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Ookubo M, Sadamatsu M, Yoshimura A, Suzuki S, Kato N, Kojima H, Yamada N, Kanai H. Aberrant Monoaminergic System in Thyroid Hormone Receptor-β Deficient Mice as a Model of Attention-Deficit/Hyperactivity Disorder. Int J Neuropsychopharmacol 2015; 18:pyv004. [PMID: 25612897 PMCID: PMC4540106 DOI: 10.1093/ijnp/pyv004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Thyroid hormone receptors are divided into 2 functional types: TRα and TRβ. Thyroid hormone receptors play pivotal roles in the developing brain, and disruption of thyroid hormone receptors can produce permanent behavioral abnormality in animal models and humans. METHODS Here we examined behavioralchanges, regional monoamine metabolism, and expression of epigenetic modulatory proteins, including acetylated histone H3 and histone deacetylase, in the developing brain of TRα-disrupted (TRα (0/0) ) and TRβ-deficient (TRβ (-/-) ) mice. Tissue concentrations of dopamine, serotonin (5-hydroxytryptamine) and their metabolites in the mesocorticolimbic pathway were measured. RESULTS TRβ (-/-) mice, a model of attention-deficit/hyperactivity disorder, showed significantly high exploratory activity and reduced habituation, whereas TRα (0/0) mice showed normal exploratory activity. The biochemical profiles of dopamine and 5-hydroxytryptamine showed significantly low dopamine metabolic rates in the caudate putamen and nucleus accumbens and overall low 5-hydroxytryptamine metabolic rates in TRβ (-/-) mice, but not in TRα (0/0) mice. Furthermore, the expression of acetylated histone H3 was low in the dorsal raphe of TRβ (-/-) mice, and histone deacetylase 2/3 proteins were widely increased in the mesolimbic system. CONCLUSIONS These findings suggest that TRβ deficiency causes dysfunction of the monoaminergic system, accompanied by epigenetic disruption during the brain maturation process.
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Affiliation(s)
| | | | | | | | | | | | | | - Hirohiko Kanai
- Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan (Drs Ookubo, Yoshimura, Yamada, and Kanai); Department of Psychiatry, Minakuchi Hospital, Shiga, Japan (Dr Ookubo); Department of Psychology and Psychiatry, Human Sciences, Kinjo Gakuin University, Aich, Japan (Dr Sadamatsu); Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan (Dr Suzuki); Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan (Dr Kato); Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan (Dr. Kojima); Department of Psychiatry, Japanese Red Cross Society Nagahama Hospital, Shiga, Japan (Dr. Kanai).
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24
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Does serotonin deficit mediate susceptibility to ADHD? Neurochem Int 2015; 82:52-68. [DOI: 10.1016/j.neuint.2015.02.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 01/18/2015] [Accepted: 02/07/2015] [Indexed: 11/21/2022]
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Motivational assessment of mice using the touchscreen operant testing system: effects of dopaminergic drugs. Psychopharmacology (Berl) 2015; 232:4043-57. [PMID: 26156636 PMCID: PMC4600476 DOI: 10.1007/s00213-015-4009-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Accepted: 06/28/2015] [Indexed: 12/29/2022]
Abstract
RATIONALE Touchscreens are widely used to examine rodent cognition. Current paradigms require animals to view stimuli and nose poke at an appropriate touchscreen location. After responding, there is little screen interaction and, as infra-red touchscreens eliminate the need for physical contact, minimal somatosensory feedback. It is therefore unclear if touchscreens can support the vigorous, repetitive responding required in paradigms like progressive ratio (PR) for assessing motivation and effort-related choice (ERC) for assessing decision-making. OBJECTIVES This study aims to adapt and validate PR and ERC for the rodent touchscreen. METHODS Male C57Bl/6 mice were trained until responding on PR stabilised. Amphetamine, sulpiride and raclopride were administered via the intraperitoneal route to modify performance. Mice were transferred to ERC and paradigm parameters adjusted to demonstrate behavioural modification. ERC reward preference was assessed by home cage choice analysis. RESULTS PR performance stabilised within seven sessions. Amphetamine (1 mg/kg) increased and raclopride (0.3 mg/kg) decreased performance by 63 and 28 %, respectively, with a 20-min injection-test interval. Sulpiride (50 mg/kg) decreased performance by 19 % following a 40-min injection-test interval. Increasing ERC operant requirements shifted responding from the operant response-dependent preferred reward towards the freely available alternative. CONCLUSIONS Vigorous, repetitive responding is sustainable in touchscreen PR and ERC and task validation mirrors non-touchscreen versions. Thus, motivation and reward-related decision-making can be measured directly with touchscreens and can be evaluated prior to cognitive testing in the same apparatus to avoid confounding by motivational factors.
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Davies W, Humby T, Trent S, Eddy JB, Ojarikre OA, Wilkinson LS. Genetic and pharmacological modulation of the steroid sulfatase axis improves response control; comparison with drugs used in ADHD. Neuropsychopharmacology 2014; 39:2622-32. [PMID: 24842408 PMCID: PMC4140762 DOI: 10.1038/npp.2014.115] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 04/10/2014] [Accepted: 05/02/2014] [Indexed: 02/08/2023]
Abstract
Maladaptive response control is a feature of many neuropsychiatric conditions, including attention deficit hyperactivity disorder (ADHD). As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase (STS) influences risk for ADHD. We examined whether deletion of the Sts gene in the 39,X(Y*)O mouse model, or pharmacological manipulation of the STS axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analog of the stop-signal reaction time task used to detect inhibitory deficits in individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a prepotent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicates that the STS axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. While the precise neurobiological mechanism(s) underlying the effects remain to be established, there is the potential for exploiting this pathway in the treatment of disorders where failures in behavioral inhibition are prominent.
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Affiliation(s)
- William Davies
- Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
| | - Trevor Humby
- Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
| | - Simon Trent
- Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
| | - Jessica B Eddy
- Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - Obah A Ojarikre
- MRC National Institute for Medical Research, London, Cardiff, UK
| | - Lawrence S Wilkinson
- Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK,School of Psychology, Cardiff University, Tower Building, Cardiff CF10 3AT, UK, Tel: +44 (0)29 2087 0357, Fax: +44 (0)29 2087 4858, E-mail:
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27
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Davies W. Sex differences in attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms. Front Neuroendocrinol 2014; 35:331-46. [PMID: 24680800 DOI: 10.1016/j.yfrne.2014.03.003] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 02/13/2014] [Accepted: 03/17/2014] [Indexed: 02/07/2023]
Abstract
Attention Deficit Hyperactivity Disorder (ADHD) is a developmental condition characterised by severe inattention, pathological impulsivity and hyperactivity; it is relatively common affecting up to 6% of children, and is associated with a risk of long-term adverse educational and social consequences. Males are considerably more likely to be diagnosed with ADHD than females; the course of the disorder and its associated co-morbidities also appear to be sensitive to sex. Here, I discuss fundamental biological (genetic and endocrine) mechanisms that have been shown to, or could theoretically, contribute towards these sexually dimorphic phenomena. Greater understanding of how and why the sexes differ with respect to ADHD vulnerability should allow us to identify and characterise novel protective and risk factors for the disorder, and should ultimately facilitate improved diagnosis, prognosis and treatment.
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Affiliation(s)
- William Davies
- Behavioural Genetics Group, Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Tower Building, Park Place, Cardiff CF10 3AT, UK; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
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28
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Trent S, Fry JP, Ojarikre OA, Davies W. Altered brain gene expression but not steroid biochemistry in a genetic mouse model of neurodevelopmental disorder. Mol Autism 2014; 5:21. [PMID: 24602487 PMCID: PMC3946266 DOI: 10.1186/2040-2392-5-21] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 02/19/2014] [Indexed: 12/02/2022] Open
Abstract
Background The 39,XY*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,XY*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,XY*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,XY*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,XY*O brain; surprisingly, the concentrations of all of these were equivalent between groups. Conclusions Our data demonstrate that the mutation in 39,XY*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,XY*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.
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Affiliation(s)
| | | | | | - William Davies
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
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Trent S, Dean R, Veit B, Cassano T, Bedse G, Ojarikre OA, Humby T, Davies W. Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder. Psychoneuroendocrinology 2013; 38:1370-80. [PMID: 23276394 PMCID: PMC3690523 DOI: 10.1016/j.psyneuen.2012.12.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 12/03/2012] [Accepted: 12/04/2012] [Indexed: 12/23/2022]
Abstract
Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,X(Y*)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,X(Y*)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,X(Y*)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,X(Y*)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,X(Y*)O model.
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Affiliation(s)
- Simon Trent
- Behavioural Genetics Group and Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
| | - Rachel Dean
- School of Psychology, Cardiff University, Cardiff, UK
| | - Bonnie Veit
- School of Psychology, Cardiff University, Cardiff, UK
| | - Tommaso Cassano
- Department of Clinical and Experimental Medicine, Medical School, University of Foggia, Foggia, Italy
| | - Gaurav Bedse
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Obah A. Ojarikre
- Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, London, UK
| | - Trevor Humby
- Behavioural Genetics Group and Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
| | - William Davies
- Behavioural Genetics Group and Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK,Corresponding author at: Henry Wellcome Building, Heath Park Campus, Cardiff CF14 4XN, UK. Tel.: +44 0 29 2068 7047; fax: +44 0 29 2068 7068.
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Leo D, Gainetdinov RR. Transgenic mouse models for ADHD. Cell Tissue Res 2013; 354:259-71. [PMID: 23681253 PMCID: PMC3785710 DOI: 10.1007/s00441-013-1639-1] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 04/15/2013] [Indexed: 12/20/2022]
Abstract
Attention-deficit hyperactivity disorder (ADHD) is a developmental disorder characterized by symptoms of inattention, impulsivity and hyperactivity that adversely affect many aspects of life. Whereas the etiology of ADHD remains unknown, growing evidence indicates a genetic involvement in the development of this disorder. The brain circuits associated with ADHD are rich in monoamines, which are involved in the mechanism of action of psychostimulants and other medications used to treat this disorder. Dopamine (DA) is believed to play a major role in ADHD but other neurotransmitters are certainly also involved. Genetically modified mice have become an indispensable tool used to analyze the contribution of genetic factors in the pathogenesis of human disorders. Although rodent models cannot fully recapitulate complex human psychiatric disorders such as ADHD, transgenic mice offer an opportunity to directly investigate in vivo the specific roles of novel candidate genes identified in ADHD patients. Several knock-out and transgenic mouse models have been proposed as ADHD models, mostly based on targeting genes involved in DA transmission, including the gene encoding the dopamine transporter (DAT1). These mutant models provided an opportunity to evaluate the contribution of dopamine-related processes to brain pathology, to dissect the neuronal circuitry and molecular mechanisms involved in the antihyperkinetic action of psychostimulants and to evaluate novel treatments for ADHD. New transgenic models mouse models targeting other genes have recently been proposed for ADHD. Here, we discuss the recent advances and pitfalls in modeling ADHD endophenotypes in genetically altered animals.
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Affiliation(s)
- Damiana Leo
- Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, Genoa, Italy,
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Trent S, Davies W. Cognitive, behavioural and psychiatric phenotypes associated with steroid sulfatase deficiency. World J Transl Med 2013; 2:1-12. [DOI: 10.5528/wjtm.v2.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 01/24/2013] [Accepted: 02/08/2013] [Indexed: 02/05/2023] Open
Abstract
The enzyme steroid sulfatase (STS) desulfates a variety of steroid compounds thereby altering their activity. STS is expressed in the skin, and its deficiency in this tissue has been linked to the dermatological condition X-linked ichthyosis. STS is also highly expressed in the developing and adult human brain, and in a variety of steroidogenic organs (including the placenta and gonads); therefore it has the potential to influence brain development and function directly and/or indirectly (through influencing the hormonal milieu). In this review, we first discuss evidence from human and animal model studies suggesting that STS deficiency might predispose to neurobehavioural abnormalities and certain psychiatric disorders. We subsequently discuss potential mechanisms that may underlie these vulnerabilities. The data described herein have potential implications for understanding the complete spectrum of clinical phenotypes associated with X-linked ichthyosis, and may indicate novel pathogenic mechanisms underlying psychological dysfunction in developmental disorders such as attention deficit hyperactivity disorder and Turner syndrome.
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Does steroid sulfatase deficiency influence postpartum psychosis risk? Trends Mol Med 2012; 18:256-62. [DOI: 10.1016/j.molmed.2012.03.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Revised: 02/29/2012] [Accepted: 03/05/2012] [Indexed: 01/25/2023]
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