DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling

Millar, J. Kirsty; Pickard, Ben; Mackie, Shaun; James, Rachel; Christie, Sheila; Buchanan, S.; Malloy, M. P.; Chubb, Jennifer E.; Huston, Elaine; Baillie, George S.; Thomson, Pippa A.; Hill, E.; Brandon, Nicholas J.; Rain, Jean-Christophe; Camargo, Luiz Miguel; Whiting, Paul J.; Houslay, Miles D.; Blackwood, Douglas; Muir, Walter; Porteous, David J.

doi:10.1126/science.1112915

Cited by 603 publications

(613 citation statements)

References 21 publications

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“…Using mice deficient in PDE4B, it has been demonstrated that this subtype plays a critical role in lipopolysaccharide-induced signaling and inflammatory responses (Ariga et al, 2004;Jin et al, 2005a). Most recently, it has been shown that PDE4B is required for the antipsychotic effect of rolipram (Siuciak et al, 2007), which is consistent with the association of this subtype with schizophrenia (Millar et al, 2005). Nevertheless, little is known about the CNS function of PDE4B.…”

Section: Discussionmentioning

confidence: 82%

“…While the roles of these variants are still not known, recent studies using mice deficient in PDE4B have shown that this subfamily plays a complementary role in the control of neutrophil function (Ariga et al, 2004) and is required for antipsychotic effects of rolipram (Siuciak et al, 2007). In addition, PDE4B also is involved in schizophrenia by interacting with the DISC1 gene, a candidate susceptibility factor for schizophrenia (Clapcote et al, 2007;Millar et al, 2005). These results indicate that PDE4B plays a significant role in CNS functions.…”

Section: Introductionmentioning

confidence: 99%

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Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Zhang

Huang

Masood

et al. 2007

Neuropsychopharmacol

158

143

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Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression-and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4BÀ/À). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4BÀ/À mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4BÀ/À mice. Compared to PDE4B + / + littermates, PDE4BÀ/À mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light-dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4BÀ/À mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4BÀ/À mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4BÀ/À mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Zhang

Huang

Masood

et al. 2007

Neuropsychopharmacol

158

143

View full text Add to dashboard Cite

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“…Haploinsufficiency has been proposed owing to the decreased expression of full-length DISC1 and the failure to detect mutant DISC1 in lymphoblastoid cell lines derived from the patients. 31 However, the available data do not completely rule out the production of mutant DISC1. It is uncertain to what extent lymphoblast expression mirrors brain expression.…”

Section: Introductionmentioning

confidence: 98%

“…[28][29][30] In addition, alterations in the interaction of DISC1 with phosphodiesterase 4B have been suggested to contribute to the pathogenesis of major mental disorders. 31 Possible outcomes of the translocation in the DISC1 gene include haploinsufficiency or the production of a mutant-truncated DISC1 protein. Haploinsufficiency has been proposed owing to the decreased expression of full-length DISC1 and the failure to detect mutant DISC1 in lymphoblastoid cell lines derived from the patients.…”

Section: Introductionmentioning

confidence: 99%

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

et al. 2007

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A strong candidate gene for schizophrenia and major mental disorders, disrupted-inschizophrenia 1 (DISC1) was first described in a large Scottish family in which a balanced chromosomal translocation segregates with schizophrenia and other psychiatric illnesses. The translocation mutation may result in loss of DISC1 function via haploinsufficiency or dominant-negative effects of a predicted mutant DISC1 truncated protein product. DISC1 has been implicated in neurodevelopment, including maturation of the cerebral cortex. To evaluate the neuronal and behavioral effects of mutant DISC1, the Tet-off system under the regulation of the CAMKII promoter was used to generate transgenic mice with inducible expression of mutant human DISC1 (hDISC1) limited to forebrain regions, including cerebral cortex, hippocampus and striatum. Expression of mutant hDISC1 was not associated with gross neurodevelopmental abnormalities, but led to a mild enlargement of the lateral ventricles and attenuation of neurite outgrowth in primary cortical neurons. These morphological changes were associated with decreased protein levels of endogenous mouse DISC1, LIS1 and SNAP-25. Compared to their sex-matched littermate controls, mutant hDISC1 transgenic male mice exhibited spontaneous hyperactivity in the open field and alterations in social interaction, and transgenic female mice showed deficient spatial memory. The results show that the neuronal and behavioral effects of mutant hDISC1 are consistent with a dominant-negative mechanism, and are similar to some features of schizophrenia. The present mouse model may facilitate the study of aspects of the pathogenesis of schizophrenia.

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“…Interestingly, a possible role of increased cAMP PDE activity in the etiology of schizophrenia has been recently suggested. Millar et al (2005) show that the disrupted in schizophrenia 1 (DISC 1) protein normally sequesters PDE4 (inhibiting activity); thus, a loss of DISC1 could result in increased PDE4 activity. To determine if decreased cAMP signaling is responsible for the effect of Gas* on PPI, we measured cAMP levels and cAMP PDE activity across several brain regions in these transgenic mice.…”

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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DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling

Cited by 603 publications

References 21 publications

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

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

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