1Mol. Cell. Biol. 2005 May 25: 4221-8
PMID15870291
TitleGeneration and characterization of Rgs4 mutant mice.
AbstractRGS proteins are negative regulators of signaling through heterotrimeric G protein-coupled receptors and, as such, are in a position to regulate a plethora of biological phenomena. However, those have just begun to be explored in vivo. Here, we describe a mouse line deficient for Rgs4, a gene normally expressed early on in discrete populations of differentiating neurons and later on at multiple sites of the central nervous system, the cortex in particular, where it is one of the most highly transcribed Rgs genes. Rgs4(lacZ/lacZ) mice had normal neural development and were viable and fertile. Behavioral testing on mutant adults revealed subtle sensorimotor deficits but, so far, supported neither the proposed status of Rgs4 as a schizophrenia susceptibility gene (by showing intact prepulse inhibition in the mutants) nor (unlike another member of the Rgs family, RGS9) a role of Rgs4 in the acute or chronic response to opioids.
SCZ Keywordsschizophrenia, schizophrenic
2Synapse 2006 Sep 60: 319-46
PMID16786561
TitlePsychosis pathways converge via D2high dopamine receptors.
AbstractThe objective of this review is to identify a target or biomarker of altered neurochemical sensitivity that is common to the many animal models of human psychoses associated with street drugs, brain injury, steroid use, birth injury, and gene alterations. Psychosis in humans can be caused by amphetamine, phencyclidine, steroids, ethanol, and brain lesions such as hippocampal, cortical, and entorhinal lesions. Strikingly, all of these drugs and lesions in rats lead to dopamine supersensitivity and increase the high-affinity states of dopamine D2 receptors, or D2High, by 200-400% in striata. Similar supersensitivity and D2High elevations occur in rats born by Caesarian section and in rats treated with corticosterone or antipsychotics such as reserpine, risperidone, haloperidol, olanzapine, quetiapine, and clozapine, with the latter two inducing elevated D2High states less than that caused by haloperidol or olanzapine. Mice born with gene knockouts of some possible schizophrenia susceptibility genes are dopamine supersensitive, and their striata reveal markedly elevated D2High states; suchgenes include dopamine-beta-hydroxylase, dopamine D4 receptors, G protein receptor kinase 6, tyrosine hydroxylase, catechol-O-methyltransferase, the trace amine-1 receptor, regulator of G protein signaling RGS9, and the RIIbeta form of cAMP-dependent protein kinase (PKA). Striata from mice that are not dopamine supersensitive did not reveal elevated D2High states; these include mice with knockouts of adenosine A2A receptors, glycogen synthase kinase GSK3beta, metabotropic glutamate receptor 5, dopamine D1 or D3 receptors, histamine H1, H2, or H3 receptors, and rats treated with ketanserin or aD1 antagonist. The evidence suggests that there are multiple pathways that convergetoelevate the D2High state in brain regions and that this elevation may elicit psychosis. This proposition is supported by the dopamine supersensitivity that is a common feature of schizophrenia and that also occurs in many types of genetically altered, drug-altered, and lesion-altered animals. Dopamine supersensitivity, in turn, correlates with D2High states. The finding that all antipsychotics, traditional and recent ones, act on D2High dopamine receptors further supports the proposition.
SCZ Keywordsschizophrenia, schizophrenic
3Synapse 2007 May 61: 303-9
PMID17318883
TitleConsistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine-treated animal model of schizophrenia and in postmortem schizophrenia brain.
AbstractIt is known that RGS9-2 gene knockout mice show supersensitivity to DA and have a marked elevation in the proportion of DA D2 receptors in the high-affinity state for DA (D2(High) receptors). As this is a similar profile to that observed in the CNS from subjects with schizophrenia, we examined whether postmortem CNS tissue from subjects with the disorder and brain striata from an animal model of psychosis or schizophrenia (the amphetamine-sensitized rat) had altered levels of RGS9-2. The mRNA for RGS9-2 in 29 control hippocampi was 0.185 +/- 0.015 fg per fg of beta-glucuronidase mRNA (average +/- SE), while that in 29 schizophrenia hippocampi was 0.145 +/- 0.015 fg per fg of beta-glucuronidase mRNA (average +/- SE), a reduction of 22%. Of the many receptor-regulating genes related to G proteins, and of 11 RGS genes, RGS9-2 was the most reduced in the amphetamine-sensitized rat striatum. The reduced levels of RGS9-2 expression in both an animal model of schizophrenia and a postmortem schizophrenia brain provide further evidence implicating RGS9-2 as a candidate gene in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
4Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Mar 150B: 239-42
PMID18548510
TitleAnalysis of genetic variations in the RGS9 gene and antipsychotic-induced tardive dyskinesia in schizophrenia.
AbstractSome patients treated chronically with antipsychotics develop tardive dyskinesia (TD), an abnormal involuntary movement disorder. Typical antipsychotics block D(2) dopamine receptors (D(2)DR) and produce D(2)DR supersensitivity. On contrary, regulators of G-protein signaling (RGS) can enhance the signal termination of G-protein-coupled D(2)DR. Besides, after prolonged inhibition of dopaminergic transmission, dopaminergic agonists induced severe dyskinesia only in RGS9 knock-out mice but not in normal mice. Therefore, variety in the human RGS9 gene may be related to susceptibility to TD. In this study, schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale twice over a 3-month interval. Only patients in whom abnormal involuntary movements were absent (non-TD group) and those who showed persistent TD (TD group) were enrolled. There were 407 patients in the study sample (TD = 252; non-TD = 155) and seven single nucleus polymorphisms (SNPs) in the RGS9 gene were genotyped for each subject. Genotype and allelic distributions of SNPs did not differ between the TD and non-TD groups in this study, with the exception that a weak trend of allelic association was seen with rs4790953 (P = 0.0399). In the haplotype analysis, a significant association of the AGG haplotype (rs8077696-rs8070231-rs2292593) of the RGS9 gene was found (permutation P = 0.007), and this is worthy of replication and further study.
SCZ Keywordsschizophrenia, schizophrenic
5Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Mar 150B: 239-42
PMID18548510
TitleAnalysis of genetic variations in the RGS9 gene and antipsychotic-induced tardive dyskinesia in schizophrenia.
AbstractSome patients treated chronically with antipsychotics develop tardive dyskinesia (TD), an abnormal involuntary movement disorder. Typical antipsychotics block D(2) dopamine receptors (D(2)DR) and produce D(2)DR supersensitivity. On contrary, regulators of G-protein signaling (RGS) can enhance the signal termination of G-protein-coupled D(2)DR. Besides, after prolonged inhibition of dopaminergic transmission, dopaminergic agonists induced severe dyskinesia only in RGS9 knock-out mice but not in normal mice. Therefore, variety in the human RGS9 gene may be related to susceptibility to TD. In this study, schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale twice over a 3-month interval. Only patients in whom abnormal involuntary movements were absent (non-TD group) and those who showed persistent TD (TD group) were enrolled. There were 407 patients in the study sample (TD = 252; non-TD = 155) and seven single nucleus polymorphisms (SNPs) in the RGS9 gene were genotyped for each subject. Genotype and allelic distributions of SNPs did not differ between the TD and non-TD groups in this study, with the exception that a weak trend of allelic association was seen with rs4790953 (P = 0.0399). In the haplotype analysis, a significant association of the AGG haplotype (rs8077696-rs8070231-rs2292593) of the RGS9 gene was found (permutation P = 0.007), and this is worthy of replication and further study.
SCZ Keywordsschizophrenia, schizophrenic
6Psychiatr. Genet. 2010 Feb 20: 47-8
PMID20016399
TitleNo association between regulator of G-protein signaling 9 (RGS9) and schizophrenia in a Jewish population.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic
7J. Neurochem. 2010 Aug 114: 739-49
PMID20477943
TitleRGS9-2 mediates specific inhibition of agonist-induced internalization of D2-dopamine receptors.
AbstractRegulator of G protein signaling 9-2 (RGS9-2), a member of the RGS family of GTPase accelerating proteins, is expressed specifically in the striatum, a brain region involved in controlling movement, motivation, mood and addiction. RGS9-2 can be found co-localized with D(2)-class dopamine receptors in medium spiny striatal neurons and altered functioning of both RGS9-2 and D(2)-like dopamine receptors have been implicated in schizophrenia, movement disorders and reward responses. Previously we showed that RGS9-2 can specifically co-localize with D(2)-dopamine receptors (D2R). Here we provide further evidence of the specificity of RGS9-2 for regulating D2R cellular functions: the expression of RGS9-2 inhibits dopamine-mediated cellular internalization of D2R, while the expression of another RGS protein, RGS4, had no effect. In addition, the agonist-mediated internalization of the G protein coupled delta opioid receptor was unaffected by RGS9-2 expression. We utilized mutant constructs of RGS9-2 to show that the RGS9-2 DEP (for Disheveled, EGL-10, Pleckstrin homology) domain and the GTPase accelerating activity of RGS9-2 were necessary for mediating specific inhibition of D2R internalization.
SCZ Keywordsschizophrenia, schizophrenic
8Curr Neuropharmacol 2011 Mar 9: 190-4
PMID21886588
TitleAssociation between the Regulator of G-protein Signaling 9 Gene and Patients with Methamphetamine Use Disorder and Schizophrenia.
AbstractThe regulator of G-protein signaling (RGS) modulates the functioning of heterotrimeric G protein. RGS9-2 is highly expressed in the striatum and plays a role in modulating dopaminergic receptor-mediated signaling cascades. Previous studies suggested that the RGS9 gene might contribute to the susceptibility to psychotic diseases. Therefore, we investigated the association between the RGS9 gene and two related dopamine psychoses, schizophrenia and methamphetamine use disorders. The subjects comprised 487 patients of schizophrenia and 464 age- and sex-matched healthy controls and 220 patients of methamphetamine use disorder and 289 controls. We genotyped two nonsynonymous polymorphisms, rs12452285 (Leu225Ser) and rs34797451 (His498Arg), of the RGS9 gene. Rs34797451 showed monomorphism in the present Japanese population, but rs12452285 showed polymorphism. There were no significant differences in genotypic or allelic distributions of rs12452285 between patients with schizophrenia and the corresponding control or between patients with methamphetamine use disorder and the corresponding control. We also analyzed the clinical features of methamphetamine use disorder. We found a significant association in allelic distribution with the phenotypes of age at first consumption (p=0.047). The present study suggested that the RGS9 gene is unlikely to play a major role in schizophrenia and methamphetamine dependence liability and/or the development of methamphetamine induced psychosis, at least in a Japanese population.
SCZ Keywordsschizophrenia, schizophrenic
9Neurochem. Res. 2016 Feb 41: 183-92
PMID26547196
TitlePerinatal Treatments with the Dopamine D2-Receptor Agonist Quinpirole Produces Permanent D2-Receptor Supersensitization: a Model of Schizophrenia.
AbstractRepeated daily treatments of perinatal rats with the dopamine D2-receptor (D2-R) agonist quinpirole for a week or more produces the phenomenon of 'priming'-gradual but long-term sensitization of D2-R. In fact a daily dose of quinpirole as low as 50 µg/kg/day is adequate for sensitizing D2-R. Primed rats as neonates and in adolescence, when acutely treated with quinpirole display enhanced eating/gnawing/nursing on dams, also horizontal locomotor activity. Between 3 and 5 weeks of age, acute quinpirole treatment of primed rats produces profound vertical jumping with paw treading-a behavior that is not observed in control rats. At later ages acute quinpirole treatment is associated with enhanced yawning, a D2-R-associated behavior. This long-term D2-R supersensitivity is believed to be life-long, despite the relatively brief period of D2-R priming near the time of birth. D2-R supersensitivity is not associated with an increase in the number or affinity of D2-R, as assessed in the striatum of rats; nor is it induced with the D3-R agonist 7-OH-DPAT. However, quinpirole-induced D2-R supersensitivity is associated with cognitive deficits, also a deficit in pre-pulse inhibition and in neurotrophic factors, and low levels of the transcript regulator of G-protein signaling (RGS) RGS9 in brain; and acute reversal of these alterations by the antipsychotic agent olanzapine. In sum, rats ontogenetically D2-R supersensitized have face validity, construct validity and predictive ability for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic