Elevated dopamine receptor-coupled Gs protein measures in mononuclear leukocytes of patients with schizophrenia

Avissar, Sofia; Barki‐Harrington, Liza; Nechamkin, Yakov; Roitman, Gregori; Schreiber, Gabriel

doi:10.1016/s0920-9964(00)00038-4

Cited by 20 publications

(10 citation statements)

References 53 publications

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“…Cyclic nucleotide signaling specifically within the ventral hippocampal formation (VHIPP) may be particularly important because VHIPP lesions and knockdown of CREB in the rodent VHIPP impair social behaviors (Kogan et al, 2000; Brightwell et al, 2005; Tseng et al, 2009). This is consistent with the fact that both cyclic nucleotide signaling deficits (Ebstein et al, 1976; Belmaker et al, 1978; Bowers and Study, 1979; Kafka et al, 1979, 1986; Hoshino et al, 1980; Garver et al, 1982; Gattaz et al, 1983; Kafka and van Kammen, 1983; Memo et al, 1983; Goldberg et al, 1984; Kanof et al, 1986, 1987, 1989; Lerer et al, 1987; Ofuji et al, 1989; Kaiya et al, 1990; Kang, 1990; Young et al, 1991, 1993, 1994; Kaiya, 1992; Cowburn et al, 1994; Avissar et al, 1997; Gurguis et al, 1997, 1999a,b; Rahman et al, 1997; Avissar et al, 2001a,b; Bacchelli et al, 2003; Edmunds et al, 2008; Kelley et al, 2008; Turetsky and Moberg, 2009; Woolfrey et al, 2009; Ji et al, 2011) and abnormalities in the VHIPP (Suddath et al, 1990; Shenton et al, 1992; Rajarethinam et al, 2001; Jessen et al, 2003; Pegues et al, 2003; Lee et al, 2004; Rametti et al, 2007; Rusch et al, 2008; Zhou et al, 2008; Ghose et al, 2009; Nesvaderani et al, 2009; Schobel et al, 2009a,b; Hall et al, 2010; Goldman et al, 2011; Zhang et al, 2011) (referred to as the anterior hippocampus in primates) are observed in patients with neuropsychiatric disorders in which social deficits are known to occur.…”

Section: Introductionsupporting

confidence: 80%

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

et al. 2016

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Despite the fact that appropriate social behaviors are vital to thriving in one’s environment, little is understood of the molecular mechanisms controlling social behaviors or how social experience sculpts these signaling pathways. Here, we determine if Phosphodiesterase 11A (PDE11A), an enzyme that is restricted to the ventral hippocampal formation (VHIPP) and that breaks down cAMP and cGMP, regulates social behaviors. PDE11 wild-type (WT), heterozygous (HT), and knockout (KO) mice were tested in various social approach assays and gene expression differences were measured by RNA sequencing. The effect of social isolation on PDE11A4 compartmentalization and subsequent social interactions and social memory was also assessed. Deletion of PDE11A triggered age- and sex-dependent deficits in social approach in specific social contexts but not others. Mice appear to detect altered social behaviors of PDE11A KO mice, because C57BL/6J mice prefer to spend time with a sex-matched PDE11A WT vs. its KO littermate; whereas, a PDE11A KO prefers to spend time with a novel PDE11A KO vs. its WT littermate. Not only is PDE11A required for intact social interactions, we found that 1 month of social isolation vs. group housing decreased PDE11A4 protein expression specifically within the membrane fraction of VHIPP. This isolation-induced decrease in PDE11A4 expression appears functional because social isolation impairs subsequent social approach behavior and social memory in a PDE11A genotype-dependent manner. Pathway analyses following RNA sequencing suggests PDE11A is a key regulator of the oxytocin pathway and membrane signaling, consistent with its pivotal role in regulating social behavior.

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Section: Introductionsupporting

confidence: 80%

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

et al. 2016

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“…The increases of peripheral immunoreactive levels of G as and/or G ai are not peculiar of patients with AN or BN, since similar alterations have been reported in subjects with bipolar disorder, 3,4 major depression 27 and schizophrenia, 10 in men at high risk for alcoholism 28 and in opioid addicts. 29 Therefore, the major challenge for future studies will be to elucidate the mechanisms by which shared peripheral abnormalities of G proteins might be involved in the pathophysiology of different psychiatric disorders.…”

Section: Discussionsupporting

confidence: 64%

“…[3][4][5][6][7] Similarly, modifications in the various subunits of G proteins have been demonstrated in both the periphery and the CNS of schizophrenic patients, [8][9][10] whereas no change has been detected in patients with panic disorder. 11 An increasing body of evidence also suggests that psychotropic drugs, upon chronic administration, may exert effects at postreceptor sites, in particular, at the level of G proteins.…”

mentioning

confidence: 99%

Altered immunoreactive levels of G proteins in peripheral mononuclear cells of patients with anorexia nervosa and bulimia nervosa

et al. 2003

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Alterations of cellular G proteins have been implicated in the pathophysiology of some psychiatric disorders. So far, no study assessed G protein function in anorexia nervosa (AN) and bulimia nervosa (BN). Therefore, we measured immunoreactive levels of G as , G ai , G aq/11 and G b protein subunits in mononuclear leukocytes of 71 drug-free women, including 25 subjects with AN, 26 individuals with BN and 20 healthy controls. As compared to healthy women, anorexic patients exhibited significantly increased levels of G ai and G b proteins, while bulimic patients had significantly increased levels of G as , G ai and G b proteins. Immunoreactive levels of peripheral G protein subunits were not significantly correlated with demographic or nutritional parameters. These findings, although obtained in peripheral blood cells, may suggest a derangement of G protein-mediated signal transduction in the pathophysiology of eating disorders.

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“…Acutely, Gas stimulates AC resulting in increased levels of cAMP ( Figure 1a; Neves et al, 2002); however, compensatory degradation of cAMP by phosphodiesterases (PDEs) counteracts chronic Gas signaling in select cell types (Figure 1a; eg Lania et al, 1998). Gas signaling is of particular interest in the study of endophenotypes of schizophrenia, because increased activity of this protein has been noted in the striatum and leukocytes of patients with schizophrenia (Memo et al, 1983;Avissar et al, 2001). Further, a polymorphism, which results in increased mRNA expression of Gas (Frey et al, 2005), has recently been genetically linked to schizophrenia (Minoretti et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Kelly

Isiegas

Cheung

et al. 2006

Neuropsychopharmacol

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Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Gas (Gas*) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Gas* causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Gas* increases cAMP levels in the striatum. Suprisingly, however, Gas* mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Gas* on PPI because Rp-cAMPS decreases PPI in C57BL/ 6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Gas* mice and the cPDE inhibitor rolipram also rescues PPI deficits of Gas* mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Gas* mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Gas*. We conclude that expression of Gas* within forebrain neurons causes PPI deficits because of a PKAdependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.

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Elevated dopamine receptor-coupled Gs protein measures in mononuclear leukocytes of patients with schizophrenia

Cited by 20 publications

References 53 publications

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

Altered immunoreactive levels of G proteins in peripheral mononuclear cells of patients with anorexia nervosa and bulimia nervosa

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

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