Abstract
Complex defects in neuronal signaling may underlie the dysfunctions that characterize schizophrenia. Using cDNA microarrays, we discovered that the transcript encoding regulator of G-protein signaling 4 (RGS4) was the most consistently and significantly decreased in the prefrontal cortex of all schizophrenic subjects examined. The expression levels of ten other RGS family members represented on the microarrays were unchanged and hierarchical data analysis revealed that as a group, 274 genes associated with G-protein signaling were unchanged. Quantitative in situ hybridization verified the microarray RGS4 data, and demonstrated highly correlated decreases in RGS4 expression across three cortical areas of ten subjects with schizophrenia. RGS4 expression was not altered in the prefrontal cortex of subjects with major depressive disorder or in monkeys treated chronically with haloperidol. Interestingly, targets for 70 genes mapped to the major schizophrenia susceptibility locus 1q21–22 were present on the microarrays, of which only RGS4 gene expression was consistently altered. The combined data indicate that a decrease in RGS4 expression may be a common and specific feature of schizophrenia, which could be due either to genetic factors or a disease- specific adaptation, both of which could affect neuronal signaling.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lewis D, Lieberman J . Catching up on schizophrenia Neuron 2000 28: 325–334
Hyman SE . The NIMH perspective: next steps in schizophrenia research Biol Psychiatry 2000 47: 1–7
Lewis DA . Is there a neuropathology of schizophrenia? The Neuroscientist 2000 6: 208–218
Pilowsky LS, Kerwin RW, Murray RM . Schizophrenia: a neurodevelopmental perspective Neuropsychopharmacology 1993 9: 83–91
Weinberger DR . From neuropathology to neurodevelopment Lancet 1995 346: 552–557
Weinberger DR, Aloia MS, Goldberg TE, Berman KF . The frontal lobes and schizophrenia J Neuropsychiatry Clin Neurosci 1994 6: 419–427
Goldman-Rakic PS, Selemon LD . Functional and anatomical aspects of prefrontal pathology in schizophrenia Schizophr Bull 1997 23: 437–458
Glantz LA, Lewis DA . Decreased dendritic spine density of prefrontal cortical pyramidal neurons in schizophrenia Arch Gen Psychiatry 2000 57: 65–73
Pettegrew JW, Keshavan MS, Panchalingam K et al. Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy Arch Gen Psychiatry 1991 48: 563–568
Mirnics K, Middleton F, Marquez A, Lewis D, Levitt P . Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex Neuron 2000 28: 53–67
Knable MB, Weinberger DR . Dopamine, the prefrontal cortex and schizophrenia J Psychopharmacol 1997 11: 123–131
Bunney WE, Bunney BG . Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia Brain Res Rev 2000 31: 138–146
Aghajanian GK, Marek GJ . Serotonin model of schizophrenia: emerging role of glutamate mechanisms Brain Res Rev 2000 31: 302–312
Berman DM, Kozasa T, Gilman AG . The GTPase-activating protein RGS4 stabilizes the transition state for nucleotide hydrolysis J Biol Chem 1996 271: 27209–27212
Berman DM, Wilkie TM, Gilman AG . GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits Cell 1996 86: 445–452
De Vries L, Zheng B, Fischer T, Elenko E, Farquhar MG . The regulator of G protein signaling family Annu Rev Pharmacol Toxicol 2000 40: 235–271
Zheng B, De Vries L, Gist Farquhar M . Divergence of RGS proteins: evidence for the existence of six mammalian RGS subfamilies Trends Biochem Sci 1999 24: 411–414
Gold SJ, Ni YG, Dohlman HG, Nestler EJ . Regulators of G-protein signaling (RGS) proteins: region-specific expression of nine subtypes in rat brain J Neurosci 1997 17: 8024–8037
De Vries L, Gist Farquhar M . RGS proteins: more than just GAPs for heterotrimeric G proteins Trends Cell Biol 1999 9: 138–144
Hoyer D, Clarke DE, Fozard JR et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin) Pharmacol Rev 1994 46: 157–203
Westbrook GL . Glutamate receptor update Curr Opin Neurobiol 1994 4: 337–346
Kerr DI, Ong J . GABAB receptors Pharmacol Ther 1995 67: 187–246
Missale C, Nash SR, Robinson SW, Jaber M, Caron MG . Dopamine receptors: from structure to function Physiol Rev 1998 78: 189–225
Seeman P, Chau-Wong M, Tedesco J, Wong K . Brain receptors for antipsychotic drugs and dopamine: direct binding assays Proc Natl Acad Sci U S A 1975 72: 4376–4380
Creese I, Burt DR, Snyder SH . Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs Science 1976 192: 481–483
Lieberman JA, Mailman RB, Duncan G et al. Serotonergic basis of antipsychotic drug effects in schizophrenia Biol Psychiatry 1998 44: 1099–1117
Brzustowicz LM, Hodgkinson KA, Chow EW, Honer WG, Bassett AS . Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22 Science 2000 288: 678–682
Volk DV, Austin MC, Pierri JN, Sampson RA, Lewis DA . Decreased GAD67 mRNA expression in a subset of prefrontal cortical GABA neurons in schizophrenia Arch Gen Psychiatry 2000 57: 237–245
Campbell DB, North JB, Hess E . Tottering mouse motor dysfunction is abolished on the Purkinje cell degeneration (pcd) mutant background Exp Neurol 1999 160: 268–278
Pierri JN, Chaudry BS, Woo TUW, Lewis DA . Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects Am J Psychiatry 1999 156: 1709–1719
Pakkenberg B . Total nerve cell number in neocortex in chronic schizophrenics and controls estimated using optical disectors Biol Psychiatry 1993 11: 768–772
Thune JJ, Pakkenberg B . Stereological studies of the schizophrenic brain Brain Res Brain Res Rev 2000 31: 200–204
Guan KL, Han M . A G-protein signaling network mediated by an RGS protein Genes Dev 1999 13: 1763–1767
Nishino N, Kitamura N, Hashimoto T et al. Increase in [3H]cAMP binding sites and decrease in Gi alpha and Go alpha immunoreactivities in left temporal cortices from patients with schizophrenia Brain Res 1993 615: 41–49
Yang CQ, Kitamura N, Nishino N, Shirakawa O, Nakai H . Isotype-specific G protein abnormalities in the left superior temporal cortex and limbic structures of patients with chronic schizophrenia Biol Psychiatry 1998 43: 12–19
Okada F, Tokumitsu Y, Takahashi N, Crow TJ, Roberts GW . Reduced concentrations of the alpha-subunit of GTP-binding protein Go in schizophrenic brain J Neural Transm Gen Sect 1994 95: 95–104
Wong DF, Wagner HN Jr, Tune LE et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics [published erratum appears in Science 1987 Feb 6; 235: 623] Science 1986 234: 1558–1563
Seeman P, Ulpian C, Bergeron C et al. Bimodal distribution of dopamine receptor densities in brains of schizophrenics Science 1984 225: 728–731
Abi-Dargham A, Rodenhiser J, Printz D et al. From the cover: increased baseline occupancy of D2 receptors by dopamine in schizophrenia Proc Natl Acad Sci U S A 2000 97: 8104–8109
Harrison PJ . The neuropathology of schizophrenia. A critical review of the data and their interpretation Brain 1999 122: 593–624
Whitney LW, Becker KG, Tresser NJ et al. Analysis of gene expression in multiple sclerosis lesions using cDNA microarrays Ann Neurol 1999 46: 425–428
Brown PO, Botstein D . Exploring the new world of the genome with DNA microarrays Nat Genet Suppl 1999 21: 33–37
Geschwind DH . Mice, microarrays, and the genetic diversity of the brain Proc Natl Acad Sci U S A 2000 97: 10676–10678
Popov SG, Krishna UM, Falk JR, Wilkie TM . Ca2+/calmodulin reverses PIP3-dependent inhibition of RGS GAP activity J Biol Chem 2000 25: 18962–18968
Cavalli A, Druey KM, Milligan G . The regulator of G protein signaling RGS4 selectively enhances alpha2A adrenoceptor stimulation of the GTPase activity of Go1alpha and Gi2alpha J Biol Chem 2000 275: 23693–23699
Xu X, Zeng W, Popov S et al. RGS proteins determine signaling specificity of Gq-coupled receptors J Biol Chem 1999 274: 3549–3556
Greengard P, Allen PB, Nairn AC . Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade Neuron 1999 23: 435–447
Friberg IK, Young AB, Standaert DG . Differential localization of the mRNAs for the pertussis toxin insensitive G-protein alpha sub-units Gq, G11, and Gz in the rat brain, and regulation of their expression after striatal deafferentation Mol Brain Res 1998 54: 298–310
Aoki C, Go CG, Wu K, Siekevitz P . Light and electron microscopic localization of alpha subunits of GTP-binding proteins, G(o) and Gi, in the cerebral cortex and hippocampus of rat brain Brain Res 1992 596: 189–201
Stockmeier CA, DiCarlo JJ, Zhang Y, Thompson P, Meltzer HY . Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin2 and dopamine2 receptors J Pharmacol Exp Ther 1993 266: 1374–1384
Seeman P, Tallerico T . Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation for low receptor occupancy and early clinical relapse upon withdrawal of clozapine or quetiapine Am J Psychiatry 1999 156: 876–884
Meltzer HY . The role of serotonin in antipsychotic drug action Neuropsychopharmacology 1999 21: 106S–115S
Pulver AE . Search for schizophrenia succeptability genes Biol Psychiatry 2000 47: 221–230
Pettegrew JW, Keshavan MS, Minshew NJ . 31P nuclear magnetic resonance spectroscopy: neurodevelopment and schizophrenia Schizophr Bull 1993 19: 35–53
Feinberg I . Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psych Res 1982 17: 317–334
Huttenlocher P . Synaptic density in human frontal cortex—developmental changes and effects of aging Brain Res 1979 163: 195–205
Bourgeois JP, Goldman-Rakic PS, Rakic P . Formation, elimination and stabilization of synapses in the primate cerebral cortex. In: Gazzaniga M (ed). The Cognitive Neurosciences Cambridge University Press: Cambridge 2001 (in press
Sams-Dodd F, Lipska BK, Weinberger DR . Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood Psychopharmacol (Berl) 1997 132: 303–310
Marcotte ER, Quirion R, Srivastava LK . Gene expression changes in adult prefrontal cortex and nucleus accumbens following neonatal ventral hippocampal lesions SFN Abstr 2000 385: 14
Acknowledgements
We are grateful to the colleagues who read and commented on earlier versions of this manuscript, as well as Dr J Pierri for his involvement in the chronic haloperidol treatment of monkeys. The research was supported by projects 1 (DAL) and 2 (PL, KM) of NIMH Center Grant MH45156 (DAL), an endowment fund from the RK Mellon Foundation (PL) and NIMH training grant T32 MH18273 (FM).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mirnics, K., Middleton, F., Stanwood, G. et al. Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry 6, 293–301 (2001). https://doi.org/10.1038/sj.mp.4000866
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4000866
Keywords
This article is cited by
-
Changes in cortical gene expression in the muscarinic M1 receptor knockout mouse: potential relevance to schizophrenia, Alzheimer’s disease and cognition
npj Schizophrenia (2021)
-
The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway
Neurotherapeutics (2021)
-
Abnormal expression of rno_circRNA_014900 and rno_circRNA_005442 induced by ketamine in the rat hippocampus
BMC Psychiatry (2020)
-
Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex
Translational Psychiatry (2020)
-
Changed frontal pole gene expression suggest altered interplay between neurotransmitter, developmental, and inflammatory pathways in schizophrenia
npj Schizophrenia (2018)