PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia

Fatemi, S. Hossein; King, David P.; Reutiman, Teri J.; Folsom, Timothy D.; Laurence, Jessica A.; Lee, Susanne; Fan, Yu-Ti; Paciga, Sara A.; Conti, Marco; Menniti, Frank S.

doi:10.1016/j.schres.2008.01.029

Cited by 125 publications

(121 citation statements)

References 57 publications

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“…PDE4B is a phosphodiesterase which has been implicated in animal models with learning and memory impairments 44,49,50 . Polymorphisms of PDE4B have been reported to be associated with schizophrenia in human GWAS 51 . Approaches with mutated human DISC1 in mice have resulted in reports of hyperlocomotion, diminished reward learning, impairments in social interaction and declarative memory and increased aggression [52][53][54] .…”

Section: Disc1mentioning

confidence: 99%

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Gottschalk

Sarnyai

Guest

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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Psychiatric symptoms are subjective by nature and tend to overlap between different disorders. The modelling of a neuropsychiatric disorder therefore faces challenges because of missing knowledge of the fundamental pathophysiology and a lack of accurate diagnostics. Animal models are used to test hypotheses of aetiology and to represent the human condition as close as possible to increase our understanding of the disease and to evaluate new targets for drug discovery. In this review, genetic and neurodevelopmental animal models of schizophrenia are discussed with respect to behavioural and neurophysiological findings and their association with the clinical condition. Only specific animal models of schizophrenia may ultimately lead to novel diagnostic approaches and drug discovery. We argue that molecular biomarkers are important to improve animal to human translation since behavioural readouts lack the necessary specificity and reliability to assess human psychiatric symptoms.Gottschalk MG, et al. / Rev Psiq Clín. 2013;40(1):41-50 Keywords: Translational research, neuropsychiatry, genetic, neurodevelopment, animal model, schizophrenia. ResumoSintomas psiquiátricos são subjetivos por natureza e tendem a se sobrepor entre diferentes desordens. Sendo assim, a criação de modelos de uma desordem neuropsiquiátrica encontra desafios pela falta de conhecimento dos fundamentos da fisiopatologia e diagnósticos precisos. Modelos animais são usados para testar hipóteses de etiologia e para representar a condição humana tão próximo quanto possível para aumentar nosso entendimento da doença e avaliar novos alvos para a descoberta de drogas. Nesta revisão, modelos animais genéticos e de neurodesenvolvimento de esquizofrenia são discutidos com respeito a achados comportamentais e neurofisiológicos e sua associação com a condição clínica. Somente modelos animais específicos de esquizofrenia podem, em último caso, levar a novas abordagens diagnósticas e descoberta de drogas. Argumentamos que biomarcadores moleculares são importantes para aumentar a tradução de animais a humanos, já que faltam a especificidade e a fidelidade necessárias às leituras comportamentais para avaliar sintomas psiquiátricos humanos.Gottschalk MG, et al. / Rev Psiq Clín. 2013;40(1):41-50

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Section: Disc1mentioning

confidence: 99%

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Gottschalk

Sarnyai

Guest

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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“…Among these targeting proteins, the interaction of PDE4B with DISC1 has received attention because DISC1 is a promising genetic susceptibility factor for schizophrenia (43,44). In addition, disruption of the PDE4B gene by a balanced translocation segregates with schizophrenia (43), and PDE4B polymorphisms are associated with schizophrenia (45). Dysregulation of cAMP/PKA signaling by a DISC1/PDE4B complex may contribute to the molecular basis underlying schizophrenia.…”

Section: Role Of Pde4 In Dopaminergic Neurotransmissionmentioning

confidence: 99%

Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Biochemical and Behavioral Profiles of Phosphodiesterase Inhibition in Dopaminergic Neurotransmission

Nishi

Snyder

2010

J Pharmacol Sci

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Abstract. Dopamine plays a central role in the regulation of psychomotor functions. The effect of dopamine is largely mediated through the cAMP/PKA signaling cascade and therefore controlled by phosphodiesterases (PDEs). Multiple PDEs with different substrate specificities and subcellular localization are expressed in the striatum, and the functional roles of PDE10A, PDE4, and PDE1B are extensively studied. Biochemical and behavioral profiles of PDE inhibition by selective inhibitors and/or genetic deletion related to dopaminergic neurotransmission are compared among those PDEs. The inhibition of PDE up-regulates cAMP/PKA signaling in three neuronal subtypes, resulting in the stimulation of dopamine synthesis at dopaminergic terminals, the inhibition of dopamine D 2 -receptor signaling in striatopallidal neurons, and the stimulation of dopamine D 1 -receptor signaling in striatonigral neurons. Predominant roles of PDE families or isoforms are implicated in each neuronal subtype: PDE4 at dopaminergic terminals, PDE10A and PDE4 in striatopallidal neurons, and PDE1B in striatonigral neurons. PDE10A and PDE4 inhibition may exhibit D 2 antagonist-like, antipsychotic effects, whereas PDE1B inhibition may exhibit D 1 agonist-like effects in the striatum. Development of PDE isoform-specific inhibitors is essential for better understanding of the function of each PDE isoform and treatment of neuropsychiatric disorders.

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“…A significant reduction of expression of isoforms 2, 3 and 4 were found in postmortem schizophrenic brain samples. 11 In addition, based on a pharmacogenomic approach, a susceptibility locus, PDE7B may serve as a predictor for treatment response to risperidone 12 in patients with schizophrenia. We recently profiled functional transcriptome of neurons from a thalamic subregion, the mediodorsal nucleus, parvocellular division (MDNp) that comprises a thalamo-cortical circuit involved in working memory, a deficit in persons suffering from schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

Chu

Liu

2010

J Hum Genet

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Schizophrenia is a highly complex inheritable disease characterized by numerous genetic susceptibility elements, each contributing a modest increase in risk for the disease. Although numerous linkage or association studies have identified a large set of schizophrenia-associated loci, many are controversial. In addition, only a small portion of these loci overlaps with the large cumulative pool of genes that have shown changes of expression in schizophrenia. Here, we applied a genomic gene-function approach to identify susceptibility loci that show direct effect on gene expression, leading to functional abnormalities in schizophrenia. We carried out an integrated analysis by cross-examination of the literature-based susceptibility loci with the schizophrenia-associated expression gene list obtained from our previous microarray study (Journal of Human Genetics (2009) 54: 665-75) using bioinformatic tools, followed by confirmation of gene expression changes using qPCR. We found nine genes (CHGB, SLC18A2, SLC25A27, ESD, C4A/C4B, TCP1, CHL1 and CTNNA2) demonstrate gene-function correlation involving: synapse and neurotransmission; energy metabolism and defense mechanisms; and molecular chaperone and cytoskeleton. Our findings further support the roles of these genes in genetic influence and functional consequences on the development of schizophrenia. It is interesting to note that four of the nine genes are located on chromosome 6, suggesting a special chromosomal vulnerability in schizophrenia.

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PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia

Cited by 125 publications

References 57 publications

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Biochemical and Behavioral Profiles of Phosphodiesterase Inhibition in Dopaminergic Neurotransmission

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

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