Genes, dopamine and cortical signal-to-noise ratio in schizophrenia

Winterer, Georg; Weinberger, Daniel R.

doi:10.1016/j.tins.2004.08.002

Cited by 562 publications

(438 citation statements)

References 68 publications

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“…23 The results reported herein are in agreement with those providing evidence of the association of the Val allele with schizophrenia. 9 Schizophrenia and schizoaffective disorders have been considered together in molecular genetic studies within a 'core' phenotype.…”

Section: Panss-t Panss-p Panss-n Panss-g Responderssupporting

confidence: 91%

“…21,22 The pathophysiological basis of the influence of COMT in the prefrontal cortex function has also been studied, with results that are in agreement with the dopaminergic hypothesis of schizophrenia. [23][24][25] Current data support the idea that other variants of the COMT gene could also be of relevance. 26 In fact, a casecontrol study carried out in a large sample of Ashkenazi Jews 27 found a highly statistically significant association between schizophrenia and two other polymorphisms of the COMT gene (rs165599 and rs737865), and another work 28 assessing the relevance of some haplotypes of the COMT gene in patients with schizophrenia belonging to different populations supports the hypothesis that the presence of some haplotypes can be associated with the differential expression from the P2 promoter, which directs the expression of the MB-COMT.…”

Section: Introductionsupporting

confidence: 56%

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Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment

et al. 2007

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Genetic variation in the catechol-O-methyltransferase (COMT) gene may influence the susceptibility to schizophrenia and the response to neuroleptic treatment. The authors tested for an association between a COMT haplotype and schizophrenia-spectrum disorders and for an eventual influence of a specific COMT genotype in the clinical outcome and in the response to treatment. The genotypes for single nucleotide polymorphisms rs737865, rs4633, rs6267, rs4680 (Val 158 Met) and rs165599 were determined in 207 patients with schizophrenia-spectrum disorders and 204 paired controls. Statistical tests for linkage disequilibrium and for case-control differences in haplotype frequencies were performed using log-linear modelling embedded within the expectation-maximization algorithm. P-values based on permutations were calculated using the software UNPHASED, and odds ratios were estimated using the SHEsis platform. The response to neuroleptic treatment was assessed by the Global Assessment of Functioning scale and the severity of psychotic symptoms by the positive and negative syndrome scale (PANSS) scale. The overall disease status was significantly associated with the T-G (Val) diplotype for rs4633-rs4680 (P ¼ 0.0049). A significant association was observed between schizophrenia, but not other related disorders, and genotypes GG (Val/Val) for rs4680 and TT for rs4633. Val/Val patients with schizophrenia showed a higher severity of the psychotic symptoms and a worse response to the neuroleptic treatment. COMT genetic variation seems to be involved in the psychotic symptomatology of the schizophreniaspectrum disorders and specifically in the narrow schizophrenia phenotype. Our results show an influence of the Val 158 Met polymorphism on the severity of psychotic symptoms and on the response to treatment.

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Section: Panss-t Panss-p Panss-n Panss-g Responderssupporting

confidence: 91%

Section: Introductionsupporting

confidence: 56%

Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment

et al. 2007

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“…17,74,104,105 The mechanism of this effect is likely related to altered dopamine signaling in PFC 106 and altered excitability of glutamate and GABA neurons. 66 Thus, broadly speaking, altered GABA function might be expected to exaggerate the effects of the COMT Val allele, and vice versa. Our statistical data suggesting an interaction of COMT and GAD1 are consistent with this prediction.…”

Section: Discussionmentioning

confidence: 99%

“…64 Thus, we now also report that variations in this gene are associated with abnormalities in cortical function that are prominent in schizophrenia and in healthy siblings at risk for schizophrenia, and that a 5 0 untranslated region (UTR) SNP affects expression in human prefrontal cortex (PFC), with a similar trend in hippocampus. Moreover, because alterations in GABA activity in brain are likely to impact on the excitability of neurons in cortical microcircuits implicated in schizophrenia, 65,66 we explored the potential interaction of GAD1 risk alleles with a functional variation in COMT, another putative susceptibility gene that impacts on cortical neuronal excitability. We present preliminary evidence of an epistatic interaction of these genes.…”

Section: Introductionmentioning

confidence: 99%

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

et al. 2007

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Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD 67 ), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5 0 flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5 0 untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.

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“…118,121,133 Thus, metabolic, emotional, and cognitive information may be assimilated at the hypothalamus, and in turn forwarded to the neocortex, resulting in the ultimate decision to eat or not to eat. An interrelation between cortical glutamatergic and ascending dopaminergic systems has also been discussed to re-evaluate the classic dopamine hypothesis of schizophrenia, 209 which may also be relevant to the CNS mechanisms of feeding as a motivated behavior. Needless to say, GABA is also important not only in cortico-subcortical circuits but also in subcortical circuits.…”

mentioning

confidence: 99%

Body weight is regulated by the brain: a link between feeding and emotion

2005

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Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

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Genes, dopamine and cortical signal-to-noise ratio in schizophrenia

Cited by 562 publications

References 68 publications

Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment

Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

Body weight is regulated by the brain: a link between feeding and emotion

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