Cytokine and growth factor involvement in schizophrenia—support for the developmental model

Nawa, Hiroyuki; Takahashi, Makoto; Patterson, Paul H.

doi:10.1038/sj.mp.4000730

Cited by 185 publications

(107 citation statements)

References 139 publications

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“…Experiments using animal models indicate that neurotrophins, particularly BDNF, play a role in neurodevelopmental disorders. 54,58,[105][106][107] Human studies showing altered BDNF levels in schizophrenic patients, both in plasma and the CNS, 54,58 suggest that changes in the expression of BDNF might contribute to the disease pathophysiology, one aspect of which is a disturbed capacity for functional plasticity in these individuals.…”

Section: Discussionmentioning

confidence: 99%

BDNF in schizophrenia, depression and corresponding animal models

2005

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Understanding the etiology and pathogenesis schizophrenia and depression is a major challenge facing psychiatry. One hypothesis is that these disorders are secondary to a malfunction of neurotrophic factors. Inappropriate neurotrophic support during brain development could lead to structural disorganisation in which neuronal networks are established in a nonoptimal manner. Inadequate neurotrophic support in adult individuals could ultimately be an underlying mechanism leading to decreased capacity of brain to adaptive changes and increased vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system (CNS). In this review, we summarize findings regarding altered BDNF in schizophrenia and depression and animal models, as well as the effects of antipsychotic and antidepressive treatments on the expression of BDNF. Molecular Psychiatry (2005) 10, 345-352.

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Section: Discussionmentioning

confidence: 99%

BDNF in schizophrenia, depression and corresponding animal models

2005

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“…There is a strong correlation between infections in mid-gestation and the incidence of schizophrenia in the offspring (reviewed in (Brown, 2006;Patterson, 2008). Cytokine induction due to abnormal immune activation, or inflammation, derails normal brain development leading to alterations in cognition in adulthood (Gilmore and Jarskog, 1997;Nawa et al, 2000;Smith et al, 2007). Recently, using a rodent maternal infection model Smith and collaborators found that maternal IL-6 induction during infection is responsible for the delayed schizophrenia-like behavior observed in the adult offspring (Smith et al, 2007).…”

Section: Neurodevelopmental Origins Of Schizophrenia: Activation Of Tmentioning

confidence: 99%

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

2009

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An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a prooxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult-exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH-oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PVinterneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, while essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redoxbalance leading to schizophrenia symptoms in late adolescence and early adulthood.

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“…This is similar to the finding of hippocampal pyramidal cell disarray reported in human schizophrenia post-mortem studies [138][139][140] . Because the influenza virus or influenza virus antibodies have not been detected in the fetal brain, it has been hypothesized that the maternal immune response alone is sufficient to generate schizophrenia-like behavioural findings in the offspring 136,[141][142][143][144][145] . At the neurotransmitter level, dysfunctions in the dopaminergic and glutamatergic system have been reported, especially in the medial prefrontal cortex and the nucleus accumbens in offspring from mothers subjected to immune challenge 123 .…”

Section: Maternal Immune Activationmentioning

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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Cytokine and growth factor involvement in schizophrenia—support for the developmental model

Cited by 185 publications

References 139 publications

BDNF in schizophrenia, depression and corresponding animal models

BDNF in schizophrenia, depression and corresponding animal models

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

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

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