Cognitive Deficits Caused by Late Gestational Disruption of Neurogenesis in Rats: a Preclinical Model of Schizophrenia

Flagstad, Peter; Glenthøj, Birte; Didriksen, Michael

doi:10.1038/sj.npp.1300625

Cited by 100 publications

(76 citation statements)

References 70 publications

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“…MAM treatment could have impaired performance on the set-shifting task by altering functioning in one or all of these brain areas. The prefrontal cortex would seem a likely candidate since several previous reports have shown that MAM treatment at gestation day 17 disrupts prefrontal morphology and function (Flagstad et al, 2005;Lavin et al, 2005;Moore et al, 2006). It is unclear as to whether difficulties in shifting attentional set are due to a failure to ignore a previously reinforced dimension or to attend to a previously irrelevant dimension.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to an impairment in EDS learning, MAM-treated animals were impaired when required to make a simple reversal of a previously acquired discrimination (for two out of three reversals). Difficulties in reversal learning have been reported within a water maze paradigm in animals treated on gestational day 15 (Leng et al, 2005) and day 17 (Flagstad et al, 2005), as well as in a maze task in animals treated at day 17 (Moore et al, 2006). The finding of a reversal learning deficit in animals treated on gestational day 17 is important since treatment at this time leads to a much more restricted deficit, both behaviorally and anatomically (Gourevitch et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…These changes are accompanied by changes in mesolimbic dopamine function, as indicated by an increased sensitivity to the behavioral and neurochemical effects of amphetamine (Ferguson and Holson, 1997;Flagstad et al, 2004). Animals exposed to MAM during gestation show impairments within cognitive domains known to be disrupted in schizophrenia, such as attention (Flagstad et al, 2005;Mohammed et al, 1986a, b;Talamini et al, 2000), long-term memory (Fiore et al, 2001(Fiore et al, , 2002Gourevitch et al, 2004;Lee and Rabe, 1992;Shimizu et al, 1991), working memory (Gourevitch et al, 2004), and behavioral flexibility (Fiore et al, 2002;Flagstad et al, 2005;Leng et al, 2005), although negative findings have also been reported in many of these domains (Flagstad et al, 2005;Jongen-Relo et al, 2004). As such, prenatal methylazoxymethanol treatment has recently attracted attention as a potential animal model of schizophrenia (Grace and Moore, 1998;Moore et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Treatment occurring on or before gestational day 15 produces widespread disruptions of brain morphology and behavior (Gourevitch et al, 2004) and it is likely that these changes are too nonspecific to serve as a useful model of schizophrenia. Treatment at gestational day 17 produces much less intense changes in brain and behavior (Gourevitch et al, 2004), and treatment at this time produces deficits within many cognitive domains known to be impaired in schizophrenia (Flagstad et al, 2004(Flagstad et al, , 2005Gourevitch et al, 2004;Moore et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Gestational Methylazoxymethanol Acetate Treatment Impairs Select Cognitive Functions: Parallels to Schizophrenia

Featherstone

Rizos

Nóbrega

et al. 2006

Neuropsychopharmacol

100

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Gestational methylazoxymethanol acetate (MAM) exposure has been suggested to produce neural and behavioral abnormalities similar to those seen in schizophrenia. In order to assess MAM treatment as a model of schizophrenia, pregnant female rats were injected with MAM (22 mg/kg) on gestational day 17 and their offspring were assessed in adulthood on a series of cognitive tasks. The first experiment involved an attentional set-shifting task, a rodent analog of the Wisconsin card sort task. In experiment 2, animals were tested on the 5-choice serial reaction time task, a rodent analog of the continuous performance task. In the final experiment animals were assessed on a differential reinforcement of low rate of responding 20 s schedule of reinforcement (DRL-20), a task that is sensitive to changes in inhibitory control. In the first experiment, MAM-treated animals required a greater number of trials than controls to successfully learn an extradimensional shift on the set-shifting task, and had difficulties in learning to reverse a previously acquired discrimination. In contrast, MAM-treated animals showed little impairment on the 5-choice task, aside from a modest but consistent increase in premature responding. Finally, MAM exposed animals showed substantial impairments in DRL performance. Post-mortem analysis of brain tissue showed significant decreases in tissue weight in the hippocampus, parietal cortex, prefrontal cortex, and dorsal striatum of MAM-treated animals. These results support the notion that MAM treatment may simulate some aspects of schizophrenic cognition.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Gestational Methylazoxymethanol Acetate Treatment Impairs Select Cognitive Functions: Parallels to Schizophrenia

Featherstone

Rizos

Nóbrega

et al. 2006

Neuropsychopharmacol

100

View full text Add to dashboard Cite

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“…Also, rats in which neurogenesis was disrupted during the late gestational have deficits in a reversal-learning paradigm of the Morris water maze and in object recognition; they also exhibit perseveration in the Porsolt forced swimming test. Additionally, deficient associative learning in the acquisition of an active avoidance paradigm, and deficits in latent inhibition, have been demonstrated (Flagstad et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Cell Proliferation is Influenced by Bulbectomy and Normalized by Imipramine Treatment in a Region-Specific Manner

Keilhoff

Becker

Grecksch

et al. 2005

Neuropsychopharmacol

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Growing evidence indicates that alterations of neuroplasticity may contribute to the pathophysiology of depression. In contrast, various antidepressants increase adult hippocampal neurogenesis and block the effects of stress. These findings result in the 'neurogenesis hypothesis of depression'. The present study seeks to determine out whether cell proliferation is altered in the hippocampus, subventricular zone (SVZ), and basolateral amygdala of adult rats exposed to bilateral olfactory bulbectomy, another established model of depression and, if so, how imipramine effects bulbectomy-induced changes of cell genesis. Bulbectomy results in a significant reduction of cell proliferation in the hippocampus and SVZ, an effect that is normalized by subchronic doses of imipramine. Moreover, an increase in cell genesis in the basolateral amygdala, which is not affected by imipramine, is demonstrated. TUNEL staining indicates an enhanced apoptosis after bulbectomy in the SVZ that cannot be reduced by imipramine. Cell death rates in the hippocampus and amygdala are not affected by bulbectomy. The opposing effects of bulbectomy and imipramine treatment in the hippocampus and amygdala demonstrate that these structures of the limbic system, both integrated in emotional processing, react quite differently with regard to neuroplasticity. Further to this, we discuss a possible link between the pathogenesis of depression and changed neuronal plasticity in the SVZ.

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Antipsychotic Agents

Ablordeppey

Ofori

2021

Burger's Medicinal Chemistry and Drug Discovery

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Schizophrenia is one of the most severe diseases of the brain and is characterized by a spectrum of symptoms including positive, negative, and cognitive symptoms. Even though schizophrenia has a low worldwide prevalence (0.4–0.7%), it is one of the most devastating diseases of the central nervous system (CNS). Despite the immense studies on schizophrenia over the years, the exact cause of the disorder remains unknown. Therefore, morbidity studies and their outcomes for schizophrenia continue to rely on descriptive definitions spelled out in the Diagnostic and Statistical Manual of Mental Disorders‐fifth edition (DSM‐5). Current pharmacotherapy of the disease involves the use of antipsychotic agents that target CNS receptors including dopamine and serotonin receptor subtypes. Despite the success in the management of psychiatric illness most of the current antipsychotics are saddled with problems such as inefficacy across patient populations and disease domains and intolerable side effects that limit their widespread utility. Evolving paradigm shift in antipsychotic drug discovery efforts over the last decade has begun to address these issues opening the door for new hypotheses that integrate well‐known neurotransmitter systems with neuronal circuits. Recent advances in molecular biology and genetics are also paving the way for a better understanding of the etiology and pathophysiology of schizophrenia. In addition to reviewing currently used agents, this article will focus on the advances made to address the stated problems and highlight the paradigm shift in the antipsychotic drug discovery area.

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Cognitive Deficits Caused by Late Gestational Disruption of Neurogenesis in Rats: a Preclinical Model of Schizophrenia

Cited by 100 publications

References 70 publications

Gestational Methylazoxymethanol Acetate Treatment Impairs Select Cognitive Functions: Parallels to Schizophrenia

Gestational Methylazoxymethanol Acetate Treatment Impairs Select Cognitive Functions: Parallels to Schizophrenia

Cell Proliferation is Influenced by Bulbectomy and Normalized by Imipramine Treatment in a Region-Specific Manner

Antipsychotic Agents

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