Skip to main content

Advertisement

SpringerLink
Log in

Cortical copper transporter expression in schizophrenia: interactions of risk gene dysbindin-1

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Schizophrenia susceptibility factor dysbindin-1 is associated with cognitive processes. Downregulated dysbindin-1 expression is associated with lower expression of copper transporters ATP7A and CTR1, required for copper transport to the central nervous system. We measured dysbindin-1 isoforms-1A and -1BC, CTR1, and ATP7A via Western blots of the postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects (n = 28) and matched controls (n = 14). In addition, we subdivided the schizophrenia group by treatment status and comorbidity of alcohol use disorder (AUD) and assessed the relationships between proteins. Schizophrenia subjects exhibited similar protein levels to that of controls, with no effect of antipsychotic treatment. We observed a shift towards more dysbindin-1A expression in schizophrenia, as revealed by the ratio of dysbindin-1 isoforms. Dysbindin-1A expression was negatively correlated with ATP7A in schizophrenia, with no correlation present in controls. AUD subjects exhibited less dysbindin-1BC and CTR1 than those without AUD. Our results, taken together with previous data, suggest that alterations in dysbindin-1 and copper transporters are brain-region specific. For example, protein levels of ATP7A, dysbindin 1BC, and CTR1 are lower in the substantia nigra in schizophrenia subjects. AUD in the DLPFC was associated with lower protein levels of dysbindin-1 and CTR1. Changes in dysbindin-1 isoform ratio and relationships appear to be prevalent in the disease, potentially impacting symptomology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

Research data will be fully available upon request.

References

  • Abrahao KP, Salinas AG, Lovinger DM (2017) Alcohol and the brain: neuronal molecular targets, synapses, and circuits. Neuron 96:1223–1238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Acs P, Komoly S (2012) Selective ultrastructural vulnerability in the cuprizone-induced experimental demyelination. Ideggyogy Sz 65:266–270

    PubMed  Google Scholar 

  • Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ, Tanzi RE, Bertram L (2008) Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 40:827–834

    Article  CAS  PubMed  Google Scholar 

  • Burdick KE, Lencz T, Funke B, Finn CT, Szeszko PR, Kane JM, Kucherlapati R, Malhotra AK (2006) Genetic variation in DTNBP1 influences general cognitive ability. Hum Mol Genet 15:1563–1568

    Article  CAS  PubMed  Google Scholar 

  • Cox MM, Tucker AM, Tang J, Talbot K, Richer DC, Yeh L, Arnold SE (2009) Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background. Genes Brain Behav 8:390–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Donohoe G, Morris DW, Clarke S, McGhee KA, Schwaiger S, Nangle JM, Garavan H, Robertson IH, Gill M, Corvin A (2007) Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: a preliminary study. Neuropsychologia 45:454–458

    Article  PubMed  Google Scholar 

  • Eastwood SL, Harrison PJ (2005) Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons. Schizophr Res 73:159–172

    Article  CAS  PubMed  Google Scholar 

  • Eisses JF, Kaplan JH (2005) The mechanism of copper uptake mediated by human CTR1: a mutational analysis. J Biol Chem 280:37159–37168

    Article  CAS  PubMed  Google Scholar 

  • Feng Y, Zhou Z, He X, Wang H, Guo X, Hao C, Guo Y, Zhen X, Li W (2008) Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia. Schizophr Res 106:218–228

    Article  PubMed  Google Scholar 

  • Garey LJ, Ong WY, Patel TS, Kanani M, Davis A, Mortimer AM, Barnes TR, Hirsch SR (1998) Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry 65:446–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glantz LA, Lewis DA (2000) Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 57:65–73

    Article  CAS  PubMed  Google Scholar 

  • Gokhale A, Vrailas-Mortimer A, Larimore J, Comstra HS, Zlatic SA, Werner E, Manvich DF, Iuvone PM, Weinshenker D, Faundez V (2015) Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor. Hum Mol Genet 24:5512–5523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gómez GI, Falcon RV, Maturana CJ, Labra VC, Salgado N, Rojas CA, Oyarzun JE, Cerpa W, Quintanilla RA, Orellana JA (2018) Heavy alcohol exposure activates astroglial hemichannels and pannexons in the hippocampus of adolescent rats: effects on neuroinflammation and astrocyte arborization. Front Cell Neurosci 12:472

    Article  PubMed  PubMed Central  Google Scholar 

  • Gregg JR, Herring NR, Naydenov AV, Hanlin RP, Konradi C (2009) Downregulation of oligodendrocyte transcripts is associated with impaired prefrontal cortex function in rats. Schizophr Res 113:277–287

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo AY, Sun J, Riley BP, Thiselton DL, Kendler KS, Zhao Z (2009) The dystrobrevin-binding protein 1 gene: features and networks. Mol Psychiatry 14:18–29

    Article  CAS  PubMed  Google Scholar 

  • Herring NR, Konradi C (2011) Myelin, copper, and the cuprizone model of schizophrenia. Front Biosci (Schol Ed) 3:23–40

    Google Scholar 

  • Keefe RS, Harvey PD (2012) Cognitive impairment in schizophrenia. Handb Exp Pharmacol 2012(213):11–37

  • Kessler RC, Nelson CB, McGonagle KA, et al (1996) The epidemiology of co-occurring addictive and mental disorders: implications for prevention and service utilization. Am J Orthopsychiatry 66(1):17–31

  • Konopaske GT, Balu DT, Presti KT, Chan G, Benes FM, Coyle JT (2018) Dysbindin-1 contributes to prefrontal cortical dendritic arbor pathology in schizophrenia. Schizophr Res 201:270–277

    Article  PubMed  PubMed Central  Google Scholar 

  • Labbe S, Zhu Z, Thiele DJ (1997) Copper-specific transcriptional repression of yeast genes encoding critical components in the copper transport pathway. J Biol Chem 272:15951–15958

    Article  CAS  PubMed  Google Scholar 

  • Lee J, Peña MM, Nose Y, Thiele DJ (2002) Biochemical characterization of the human copper transporter Ctr1. J Biol Chem 277:4380–4387

    Article  CAS  PubMed  Google Scholar 

  • Meier MH, Caspi A, Reichenberg A, Keefe RS, Fisher HL, Harrington H, Houts R, Poulton R, Moffitt TE (2014) Neuropsychological decline in schizophrenia from the premorbid to the postonset period: evidence from a population-representative longitudinal study. Am J Psychiatry 171:91–101

    Article  PubMed  PubMed Central  Google Scholar 

  • Mirza SP, Halligan BD, Greene AS, Olivier M (2007) Improved method for the analysis of membrane proteins by mass spectrometry. Physiol Genomics 30:89–94

    Article  CAS  PubMed  Google Scholar 

  • Mullin AP, Gokhale A, Larimore J, Faundez V (2011) Cell biology of the BLOC-1 complex subunit dysbindin, a schizophrenia susceptibility gene. Mol Neurobiol 44:53–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Numakawa T, Yagasaki Y, Ishimoto T, Okada T, Suzuki T, Iwata N, Ozaki N, Taguchi T, Tatsumi M, Kamijima K, Straub RE, Weinberger DR, Kunugi H, Hashimoto R (2004) Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet 13:2699–2708

    Article  CAS  PubMed  Google Scholar 

  • Ohnuma T, Augood SJ, Arai H, McKenna PJ, Emson PC (1998) Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. Brain Res Mol Brain Res 56:207–217

    Article  CAS  PubMed  Google Scholar 

  • Papaleo F, Yang F, Garcia S, Chen J, Lu B, Crawley JN, Weinberger DR (2012) Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry 17:85–98

    Article  CAS  PubMed  Google Scholar 

  • Perez-Becerril C, Morris AG, Mortimer A, McKenna PJ, de Belleroche J (2014) Allelic variants in the zinc transporter-3 gene, SLC30A3, a candidate gene identified from gene expression studies, show gender-specific association with schizophrenia. Eur Psychiatry 29:172–178

    Article  CAS  PubMed  Google Scholar 

  • Pleil KE, Lowery-Gionta EG, Crowley NA, Li C, Marcinkiewcz CA, Rose JH, McCall NM, Maldonado-Devincci AM, Morrow AL, Jones SR, Kash TL (2015) Effects of chronic ethanol exposure on neuronal function in the prefrontal cortex and extended amygdala. Neuropharmacology 99:735–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Regier DA, Farmer ME, Rae DS et al (1990) Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. J Am Med Assoc 264(19):2511–2518

  • Ripke, S., Walters, J. T. R. and O’Donovan, M. C. 2020. Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia. medRxiv, 2020.09.12.20192922.

  • Roussos P, Katsel P, Davis KL, Siever LJ, Haroutunian V (2012) A system-level transcriptomic analysis of schizophrenia using postmortem brain tissue samples. Arch Gen Psychiatry 69:1205–1213

    Article  PubMed  Google Scholar 

  • Scarr E, Udawela M, Greenough MA, Neo J, Suk SeoMoneyUpadhyayBushEverallThomasDean MTTAAIIPEAB (2016) Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia. NPJ Schizophr 2:16002

    Article  PubMed  PubMed Central  Google Scholar 

  • Scheiber IF, Mercer JF, Dringen R (2010) Copper accumulation by cultured astrocytes. Neurochem Int 56:451–460

    Article  CAS  PubMed  Google Scholar 

  • Schizophrenia Working Group of the Psychiatric Genomics, C (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427

    Article  Google Scholar 

  • Schoonover, K. E., Queern, S. L., Lapi, S. E. and Roberts, R. C. 2018 Impaired copper transport in schizophrenia results in a copper-deficient brain state: a new side to the dysbindin story. World J Biol Psychiatry, 1–37.

  • Schoonover KE, Dienel SJ, Lewis DA (2020) Prefrontal cortical alterations of glutamate and GABA neurotransmission in schizophrenia: Insights for rational biomarker development. Biomark Neuropsychiatry 3:100015. https://doi.org/10.1016/j.bionps.2020.100015

  • Speers AE, Blackler AR, Wu CC (2007) Shotgun analysis of integral membrane proteins facilitated by elevated temperature. Anal Chem 79:4613–4620

    Article  CAS  PubMed  Google Scholar 

  • Stan AD, Ghose S, Gao XM, Roberts RC, Lewis-Amezcua K, Hatanpaa KJ, Tamminga CA (2006) Human postmortem tissue: What quality markers matter? Brain Res 1123:1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takao K, Toyama K, Nakanishi K, Hattori S, Takamura H, Takeda M, Miyakawa T, Hashimoto R (2008) Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. Mol Brain 1:11

    Article  PubMed  PubMed Central  Google Scholar 

  • Talbot K, Eidem WL, Tinsley CL, Benson MA, Thompson EW, Smith RJ, Hahn CG, Siegel SJ, Trojanowski JQ, Gur RE, Blake DJ, Arnold SE (2004) Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 113:1353–1363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Talbot K, Cho DS, Ong WY, Benson MA, Han LY, Kazi HA, Kamins J, Hahn CG, Blake DJ, Arnold SE (2006) Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. Hum Mol Genet 15:3041–3054

    Article  CAS  PubMed  Google Scholar 

  • Talbot K, Louneva N, Cohen JW, Kazi H, Blake DJ, Arnold SE (2011) Synaptic dysbindin-1 reductions in schizophrenia occur in an isoform-specific manner indicating their subsynaptic location. PLoS One 6:e16886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang J, Legros RP, Louneva N, Yeh L, Cohen JW, Hahn CG, Blake DJ, Arnold SE, Talbot K (2009) Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. Hum Mol Genet 18:3851–3863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vidović B, Dorđević B, Milovanović S, Škrivanj S, Pavlović Z, Stefanović A, Kotur-Stevuljević J (2013) Selenium, zinc, and copper plasma levels in patients with schizophrenia: relationship with metabolic risk factors. Biol Trace Elem Res 156:22–28

    Article  PubMed  Google Scholar 

  • Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M, Grouios C, Kazi F, Lopes CT, Maitland A, Mostafavi S, Montojo J, Shao Q, Wright G, Bader GD, Morris Q (2010) The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res 38:W214–W220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weickert CS, Straub RE, McClintock BW, Matsumoto M, Hashimoto R, Hyde TM, Herman MM, Weinberger DR, Kleinman JE (2004) Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 61:544–555

    Article  CAS  PubMed  Google Scholar 

  • Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, Kim NS, Yoon KJ, Shin J, Zhang C, Makri G, Nauen D, Yu H, Guzman E, Chiang CH, Yoritomo N, Kaibuchi K, Zou J, Christian KM, Cheng L, Ross CA, Margolis RL, Chen G, Kosik KS, Song H, Ming GL (2014) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515:414–418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wessman J, Paunio T, Tuulio-Henriksson A, Koivisto M, Partonen T, Suvisaari J, Turunen JA, Wedenoja J, Hennah W, Pietiläinen OP, Lönnqvist J, Mannila H, Peltonen L (2009) Mixture model clustering of phenotype features reveals evidence for association of DTNBP1 to a specific subtype of schizophrenia. Biol Psychiatry 66:990–996

    Article  CAS  PubMed  Google Scholar 

  • Wolf C, Jackson MC, Kissling C, Thome J, Linden DE (2011) Dysbindin-1 genotype effects on emotional working memory. Mol Psychiatry 16:145–155

    Article  CAS  PubMed  Google Scholar 

  • Xu H, Yang HJ, McConomy B, Browning R, Li XM (2010) Behavioral and neurobiological changes in C57BL/6 mouse exposed to cuprizone: effects of antipsychotics. Front Behav Neurosci 4:8

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi Y, Heiny ME, Gitlin JD (1993) Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. Biochem Biophys Res Commun 197:271–277

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi Y, Heiny ME, Suzuki M, Gitlin JD (1996) Biochemical characterization and intracellular localization of the Menkes disease protein. Proc Natl Acad Sci U S A 93:14030–14035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang HJ, Wang H, Zhang Y, Xiao L, Clough RW, Browning R, Li XM, Xu H (2009) Region-specific susceptibilities to cuprizone-induced lesions in the mouse forebrain: implications for the pathophysiology of schizophrenia. Brain Res 1270:121–130

    Article  CAS  PubMed  Google Scholar 

  • Yang P, Tao R, He C, Liu S, Wang Y, Zhang X (2018) The risk factors of the alcohol use disorders-through review of its comorbidities. Front Neurosci 12:303

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Q, Pangrsic T, Kreft M, Krzan M, Li N, Sul JY, Halassa M, van Bockstaele E, Zorec R, Haydon PG (2004) Fusion-related release of glutamate from astrocytes. J Biol Chem 279:12724–12733

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Xu H, Jiang W, Xiao L, Yan B, He J, Wang Y, Bi X, Li X, Kong J, Li XM (2008) Quetiapine alleviates the cuprizone-induced white matter pathology in the brain of C57BL/6 mouse. Schizophr Res 106:182–191

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the Alabama Brain Collection and Maryland Brain Collection staff for the samples used in this study and thank the brain donors and their families.

Funding

The current study was supported by the National Institute of Neurological Disorders and Stroke F99NS105208 to Dr. Schoonover and the National Institute of Mental Health R21117434 to Dr. Roberts. The authors have declared no conflicts of interest concerning this study.

Author information

Authors and Affiliations

  1. Department of Psychology and Behavioral Neuroscience, The University of Alabama at Birmingham, 3811 O’Hara Street BST W1651, Pittsburgh, PA, 15213, USA

    Kirsten E. Schoonover

  2. Department of Psychiatry and Behavioral Neurobiology, The University of Alabama at Birmingham, Pittsburgh, USA

    William M. Kennedy & Rosalinda C. Roberts

Authors
  1. Kirsten E. Schoonover
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William M. Kennedy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosalinda C. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Authors Schoonover and Roberts were responsible for the conception, analysis, interpretation, drafting, and revising of the manuscript. Authors Schoonover and Kennedy were responsible for data acquisition. All authors approved the manuscript and are accountable for all aspects of the work discussed herein.

Corresponding author

Correspondence to Kirsten E. Schoonover.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schoonover, K.E., Kennedy, W.M. & Roberts, R.C. Cortical copper transporter expression in schizophrenia: interactions of risk gene dysbindin-1. J Neural Transm 128, 701–709 (2021). https://doi.org/10.1007/s00702-021-02333-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-021-02333-z

Keywords

Search

Navigation