Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia

Castner, Stacy A.; Goldman‐Rakic, Patricia S.; Williams, Graham V.

doi:10.1007/s00213-003-1710-9

Cited by 185 publications

(104 citation statements)

References 214 publications

(193 reference statements)

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“…The neurophysiological basis of WM has also been widely investigated, and the importance of dopamine in regulating WM consistently reported (Castner, Goldman-Rakic, & Williams, 2004;Goldman-Rakic, 1999). Neuropharmacological models are increasingly moving towards an integrated view of schizophrenia as a disorder of regulation and interaction of dopaminergic and glutamatergic systems (Moghaddam & Krystal, 2003).…”

Section: Discussionmentioning

confidence: 99%

Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study

et al. 2007

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Susceptibility genes for schizophrenia have been hypothesised to mediate liability for the disorder at least partly by influencing cognitive performance. We investigated the association between genotype and cognitive performance for a Dysbindin risk haplotype which is associated with schizophrenia in our sample. Fifty-two patients with schizophrenia or schizoaffective disorder (24 risk haplotypes carriers versus 28 non-risk haplotype carriers) were assessed in areas of cognition showing evidence of familial deficits in schizophrenia. Verbal and spatial memory, working memory, and attentional control was assessed using selected measures from the Weschler memory scale (WMS), Cambridge automated test battery (CANTAB), continuous performance test (CPT), and a simple go/no-go task. Pre-morbid IQ was also assessed using the Weschler Test of Adult Reading (WTAR). Patients carrying the Dysbindin risk haplotype showed significantly lower spatial working memory performance than patients who were non-risk carriers, with genotype explaining 12% of variance in performance. Our study suggests that the increased risk for schizophrenia associated with dysbindin may be partly mediated by its influence on pre-frontal function.

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Section: Discussionmentioning

confidence: 99%

Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study

et al. 2007

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“…A hyperdopaminergic state of the ventral striatum can be a consequence of a primary PFC dysfunction of glutamatergic signaling as has been suggested by several authors (27,28). Working memory assays are often used as a behavioral read-out of PFC integrity, in humans, nonhuman primates, and rodents (29). We first examined spatial learning and long-term memory abilities by using the standard version of the Morris water maze task.…”

Section: Enhanced Dopamine Turnover In the Ventral Striatum Of Aph1bcmentioning

confidence: 94%

Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment

Dejaegere

Serneels

Schäfer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Regulated intramembrane proteolysis by ␥-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different ␥-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-␥-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-␥-secretase. We demonstrate here that the Aph1B/C-␥-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level we find accumulation of Nrg1 fragments in the brain of Aph1BC ؊/؊ mice. Our observations gain clinical relevance by the demonstration that a Val-to-Leu mutation in the Nrg1 transmembrane domain, associated with increased risk for schizophrenia, affects ␥-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders.Alzheimer's ͉ knockout ͉ schizophrenia ͉ presenilin ͉ prepulse inhibition

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“…Repeated administration of psychostimulants has been shown to model important neurobiological, behavioral, and cognitive aspects of schizophrenia, including a sensitized mesolimbic dopamine system and impairments in attentional performance Goldman-Rakic, 1999, 2003;Castner et al, 2004Castner et al, , 2005Crider et al, 1982;Dalley et al, 2005;Featherstone et al, 2007;Fletcher et al, 2005Fletcher et al, , 2007Kapur, 2003;Martinez et al, 2005;Robinson and Becker, 1986;Russig et al, 2002;Tenn et al, 2003Tenn et al, , 2005. Based on extensive evidence indicating the crucial role of the cortical cholinergic input system for attention Parikh et al, 2007;Sarter et al, 2006Sarter et al, , 2005a, the attentional symptoms of schizophrenia have been proposed to be mediated via abnormalities in the regulation and activity of this neuronal system Raedler et al, 2003Raedler et al, , 2007Sarter et al, 2005b).…”

Section: Introductionmentioning

confidence: 99%

Detection of the Moderately Beneficial Cognitive Effects of Low-Dose Treatment with Haloperidol or Clozapine in an Animal Model of the Attentional Impairments of Schizophrenia

Martı́nez

Sarter

2007

Neuropsychopharmacol

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The absence of effective cognition enhancers for the treatment of patients with schizophrenia limits the validation of animal models and behavioral tests used for drug finding and characterization. However, low doses of haloperidol and clozapine were documented to produce moderately beneficial effects in patients. Therefore, this experiment was designed to determine the attentional effects of such treatments in a repeated-amphetamine (AMPH) animal model. Animals were trained in an operant-sustained attention task and underwent a 40-day pretreatment period with saline or increasing doses (1-10 mg per kg) of AMPH. After regaining baseline performance following 10 days of saline treatment, animals were treated with haloperidol (0.025 mg per kg), clozapine (2.5 mg per kg), or vehicle for 10 days. Furthermore, the effects of AMPH challenges (1.0 mg per kg) were assessed. In AMPH-pretreated animals, the administration of AMPH challenges resulted in the disruption of attentional performance. Treatment with haloperidol and clozapine attenuated the detrimental performance effects of these challenges, with clozapine exhibiting more robust attenuation. Furthermore, clozapine, but not haloperidol, impaired the performance of control animals. In contrast, the performance of AMPH-pretreated animals remained unaffected by clozapine. As this animal model detects the moderately beneficial cognitive effects of haloperidol and clozapine, it may be useful for preclinical research designed to detect and characterize treatments for the cognitive symptoms of schizophrenia.

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Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia

Cited by 185 publications

References 214 publications

Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study

Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study

Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment

Detection of the Moderately Beneficial Cognitive Effects of Low-Dose Treatment with Haloperidol or Clozapine in an Animal Model of the Attentional Impairments of Schizophrenia

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