Skip to main content

Advertisement

SpringerLink
Log in

Quantitative Multi-modal Brain Autoradiography of Glutamatergic, Dopaminergic, Cannabinoid, and Nicotinic Receptors in Mutant Disrupted-In-Schizophrenia-1 (DISC1) Mice

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

Disrupted-in-schizophrenia-1 (DISC1) is a promising genetic susceptibility factor for major psychiatric conditions, such as schizophrenia. We hypothesized that the mutant DISC1 alters the homeostasis of multi-receptor interactions between dopaminergic [dopamine 2/3 (D2/3R)], glutamatergic [metabotropic glutamate 5 (mGluR5)], cannabinoid 1 (CB1R), and nicotinic acetylcholine (α4β2-nAChR) receptors in the brains of mice with inducible forebrain neuronal expression of dominant-negative mutant DISC1.

Procedures

The quantitative in vitro autoradiography was performed with positron emission tomography (PET) ligands using [11C]raclopride (D2/3R), [11C]ABP688 (mGluR5), [11C]OMAR (CB1R), and [18F]AZAN (nAChR). Total binding (pmol/cc) from standard and binding index, defined as [(region of interest − reference) / reference], was analyzed in the parasagittal sections. The cerebellum was used as a reference for D2/3R, mGluR5, and α4β2-nAChR, while the midbrain was the reference tissue for CB1R, because of the high density of CB1R in the cerebellum.

Results

We observed a significant positive correlation between mGluR5 and D2/3R in the nucleus accumbens (NAc) in mutant DISC1 (rho = 0.6, p = 0.04; y = 0.02 x + 6.7) and a trend of negative correlation between those receptors in the dorsal striatum (DS) in control animals (rho = −0.5, p = 0.09; y = −0.03 x + 23), suggesting a co-release of dopamine (DA) and glutamate (Glu) in the NAc, but not in the DS. There were trends of an inverse relationship between striatal CB1R and D2/3R (rho = −0.7, p = 0.07) as well as between dorsal thalamic nAChR and striatal D2/3R (rho = −0.5, p = 0.08). There was no statistically significant difference of the individual receptor density in the majority of brain regions.

Conclusions

The mutant DISC1 altered the homeostasis of multi-receptor interactions of coincident signaling of DA and Glu in the NAc, but not in the DS, and mutually negative control of striatal CB1R and D2/3R. Multi-receptor mapping with PET ligands in relevant animal models could be a valuable translational approach for psychiatric drug development.

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
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

BI:

Binding index

CB1R:

Cannabinoid 1 receptor

DISC1:

Disrupted-in-schizophrenia-1

D2/3R:

Dopamine 2/3 receptor

DLU:

Digital light unit

DS:

Dorsal striatum

GABA:

Gamma amino butyric acid

K d :

Dissociation constant

mGluR5 :

Metabotropic glutamate receptor 5

NAc:

Nucleus accumbens

nAChR:

Nicotinic acetylcholine receptor

PET:

Positron emission tomography

PFC:

Prefrontal cortex

ROI:

Region of interest

SN:

Substantia nigra

TB:

Total binding

SCZ:

Schizophrenia

VGLUT2:

Vesicular glutamate transporter 2

VMAT2:

Vesicular monoamine transporter 2

VTA:

Ventral tegmental area

VS:

Ventral striatum

References

  1. Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Millar JK, Christie S, Anderson S et al (2001) Genomic structure and localisation within a linkage hotspot of disrupted in schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry 6:173–178

    Article  CAS  PubMed  Google Scholar 

  3. Chubb JE, Bradshaw NJ, Soares DC et al (2008) The DISC locus in psychiatric illness. Mol Psychiatry 13:36–64

    Article  CAS  PubMed  Google Scholar 

  4. Pletnikov MV, Ayhan Y, Nikolskaia O et al (2008) Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry 13:173–186

    Article  CAS  PubMed  Google Scholar 

  5. Sawa A, Snyder SH (2002) Schizophrenia: diverse approaches to a complex disease. Science 296:692–695

    Article  CAS  PubMed  Google Scholar 

  6. Dal Bo G, St-Gelais F, Danik M et al (2004) Dopamine neurons in culture express VGLUT2 explaining their capacity to release glutamate at synapses in addition to dopamine. J Neurochem 88:1398–1405

    Article  CAS  PubMed  Google Scholar 

  7. Joyce MP, Rayport S (2000) Mesoaccumbens dopamine neuron synapses reconstructed in vitro are glutamatergic. Neuroscience 99(3):445–456

    Article  CAS  PubMed  Google Scholar 

  8. Chuhma N, Choi WY, Mingote S et al (2009) Dopamine neuron glutamate cotransmission: frequency-dependent modulation in the mesoventromedial projection. Neuroscience 164:1068–1083

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Hnasko TS, Chuhma N, Zhang H et al (2010) Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron 65:643–656

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Stuber GD, Hnasko TS, Britt JP et al (2010) Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate. J Neurosci 30:8229–8233

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Houchi H, Babovic D, Pierrefiche O et al (2005) CB1 receptor knockout mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors. Neuropsychopharmacology 30:339–349

    Article  CAS  PubMed  Google Scholar 

  12. Thanos PK, Gopez V, Delis F et al (2011) Upregulation of cannabinoid type 1 receptors in dopamine D2 receptor knockout mice is reversed by chronic forced ethanol consumption. Alcohol Clin Exp Res 35:19–27

    Article  PubMed Central  PubMed  Google Scholar 

  13. Mansvelder HD, McGehee DS (2002) Cellular and synaptic mechanisms of nicotine addiction. J Neurobiol 53:606–617

    Article  CAS  PubMed  Google Scholar 

  14. Strome EM, Jivan S, Doudet DJ (2005) Quantitative in vitro phosphor imaging using [3H] and [18F] radioligands: the effects of chronic desipramine treatment on serotonin 5-HT2 receptors. J Neurosci Methods 141:143–154

    Article  CAS  PubMed  Google Scholar 

  15. Farde L, Ehrin E, Eriksson L et al (1985) Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc Natl Acad Sci U S A 82:3863–3867

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Ametamey SM, Kessler LJ, Honer M et al (2006) Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5. J Nucl Med 47:698–705

    CAS  PubMed  Google Scholar 

  17. Horti AG, Fan H, Kuwabara H et al (2006) 11C-JHU75528: a radiotracer for PET imaging of CB1 cannabinoid receptors. J Nucl Med 47:1689–1696

    CAS  PubMed  Google Scholar 

  18. Horti AG, Gao Y, Kuwabara H et al (2010) Development of radioligands with optimized imaging properties for quantification of nicotinic acetylcholine receptors by positron emission tomography. Life Sci 86:575–584

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Farde L, Hall H, Ehrin E, Sedvall G (1986) Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231:258–261

    Article  CAS  PubMed  Google Scholar 

  20. Wong DF, Wagner HN Jr, Tune LE et al (1986) Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234:1558–1563

    Article  CAS  PubMed  Google Scholar 

  21. Laurelle M, Kegeles L, Abi-Dargham A (2003) Glutamate, dopamine, and schizophrenia from pathophysiology to treatment. Ann N Y Acad Sci 1003:138–158

    Article  Google Scholar 

  22. Jaaro-Peled H, Niwa M, Foss CA et al (2013) Subcortical dopaminergic deficits in a DISC1 mutant model: a study in direct reference to human molecular brain imaging. Hum Mol Genet 22:1574–1580

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Kim SJ, Sullivan JM, Wang S et al (2014) Voxelwise lp-ntPET for detecting localized, transient dopamine release of unknown timing: sensitivity analysis and application to cigarette smoking in the PET scanner. Hum Brain Mapp 35:4876–4891

    Article  PubMed Central  PubMed  Google Scholar 

  24. Niwa M, Jaaro-Peled H, Tankou S et al (2013) Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids. Science 339:335–339

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Hayashi-Takagi A, Takaki M, Graziane N et al (2010) Disrupted-in-schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci 13:327–332

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. O’Donnell P, Grace AA (1995) Synaptic interactions among excitatory afferents to nucleus accumbens neurons: hippocampal gating of prefrontal cortical input. J Neurosci 15:3622–3639

    PubMed  Google Scholar 

  27. Corti C, Xuereb JH, Crepaldi L et al (2011) Altered levels of glutamatergic receptors and Na(+)/K(+) ATPase-alpha1 in the prefrontal cortex of subjects with schizophrenia. Schizophr Res 128:7–14

    Article  PubMed  Google Scholar 

  28. Tokunaga M, Seneca N, Shin RM et al (2009) Neuroimaging and physiological evidence for involvement of glutamatergic transmission in regulation of the striatal dopaminergic system. J Neurosci 29:1887–1896

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 24(511):421–427

    Google Scholar 

  30. Ishikawa M, Okata M, Huang YH et al (2013) Dopamine triggers heterosynaptic plasticity. J Neurosci 33:6759–6765

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Saito A, Ballinger MD, Pletnikov MV et al (2013) Endocannabinoid system: potential novel targets for treatment of schizophrenia. Neurobiol Dis 53:10–17

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Pickel VM, Chan J, Kearn CS, Mackie K (2006) Targeting dopamine D2 and cannabinoid-1 (CB1) receptors in rat nucleus accumbens. J Comp Neurol 495:299–313

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Mackie K (2005) Cannabinoid receptor homo- and heterodimerization. Life Sci 77:1667–1673

    Article  CAS  PubMed  Google Scholar 

  34. Martin AB, Fernandez-Espejo E, Ferrer B et al (2008) Expression and function of CB1 receptor in the rat striatum: localization and effects on D1 and D2 dopamine receptor-mediated motor behaviors. Neuropsychopharmacology 33:1667–1679

    Article  CAS  PubMed  Google Scholar 

  35. Moldrich G, Wenger T (2000) Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study. Peptides 21:1735–1742

    Article  CAS  PubMed  Google Scholar 

  36. Marcellino D, Carriba P, Filip M et al (2008) Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis. Neuropharmacology 54:815–823

    Article  CAS  PubMed  Google Scholar 

  37. Wong DF, Kuwabara H, Kim J et al (2013) PET imaging of high-affinity α4β2 nicotinic acetylcholine receptors in humans with [18F]AZAN, a radioligand with optimal brain kinetics. J Nucl Med 54:1308–1448

    Article  CAS  PubMed  Google Scholar 

  38. Breese CR, Lee MJ, Adams CE et al (2000) Abnormal regulation of high affinity nicotine receptors in subjects with schizophrenia. Neuropsychopharmacology 23:351–364

    Article  CAS  PubMed  Google Scholar 

  39. Robinson TE, Becker JB (1985) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res Rev 11:157–198

    Article  Google Scholar 

  40. Malmberg A, Jerning E, Mohell N (1996) Critical reevaluation of spiperone and benzamide binding to dopamine D2 receptors: evidence for identical binding sites. Eur J Pharmacol 303:123–128

    Article  CAS  PubMed  Google Scholar 

  41. Farde L, Eriksson L, Blomquist G et al (1989) Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET–a comparison to the equilibrium analysis. J Cereb Blood Flow Metab 9:696–708

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by ARRA RO1NIMH (MVP), NARSAD (MVP, AK), NH094268 (MVP, AK), and NIH (NIBIB, NIDA, and NIAAA) Training grant for Clinician Scientists in Imaging Research (5T32EB006351-05) (JK), NIDA 5R33DA016182-05 (W.B.M). The authors would like to thank Drs Adjmal Nahimi (Aarhus University, Aarhus, Denmark) and Albert H. Gjedde (University of Copenhagen, Denmark) for the protocol for autoradiography and Emily Gean for her assistance with the preparation of this manuscript.

Author Contribution

Contributing to conception and design: JK, MVP, and DFW; acquiring data: HV, AH, WBM, DPH, HTR, and RFD; analyzing and interpreting data: JK, LZ, and BZ; drafting the manuscript: JK, MVP, and AK; enhancing intellectual content: VP, JRB, and AK; approving the final content of the manuscript: MVP and DFW.

Conflict of Interest

The authors declare they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Division of Nuclear Medicine, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, 601 North Caroline St. JHOC building Rm 3245, Baltimore, MD, 21287-0807, USA

    Jongho Kim, Andrew G. Horti, William B. Mathews, Heather Valentine, James R. Brasic, Daniel P. Holt, Hayden T. Ravert, Robert F. Dannals & Dean F. Wong

  2. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Vladimir Pogorelov, Atsushi Kamiya, Mikhail V. Pletnikov & Dean F. Wong

  3. Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Mikhail V. Pletnikov & Dean F. Wong

  4. Molecular Comparative Pathology, Program in Cellular and Molecular Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Mikhail V. Pletnikov

  5. Johns Hopkins School of Public Health, Baltimore, MD, USA

    Dean F. Wong

  6. Applied Mathematics and Statistics, Center for Imaging Science, Johns Hopkins University, Baltimore, MD, USA

    Luewi Zhou & Bruno Jedynak

Authors
  1. Jongho Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew G. Horti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William B. Mathews
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vladimir Pogorelov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Heather Valentine
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James R. Brasic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel P. Holt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hayden T. Ravert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Robert F. Dannals
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luewi Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bruno Jedynak
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Atsushi Kamiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mikhail V. Pletnikov
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Dean F. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dean F. Wong.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 379 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, J., Horti, A.G., Mathews, W.B. et al. Quantitative Multi-modal Brain Autoradiography of Glutamatergic, Dopaminergic, Cannabinoid, and Nicotinic Receptors in Mutant Disrupted-In-Schizophrenia-1 (DISC1) Mice. Mol Imaging Biol 17, 355–363 (2015). https://doi.org/10.1007/s11307-014-0786-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-014-0786-4

Key words

Search

Navigation