Cognitive Dysfunction in Schizophrenia

Lewis, David A.; Moghaddam, Bita

doi:10.1001/archneur.63.10.1372

Cited by 365 publications

(124 citation statements)

References 40 publications

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“…Due to their high prevalence, robustness, and severity, working memory deficits have been proposed as a core component to the diagnosis (Mesholam-Gately et al 2009). Further, these impairments critically contribute to other symptoms and neuropsychological deficits in schizophrenia (Silver et al 2003; Lewis and Moghaddam 2006).…”

Section: The Measurement and Treatment Research To Improve Cognition mentioning

confidence: 99%

“…There are three identified ionotropic receptors: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate receptors (Lewis and Moghaddam 2006). All three types of ionotropic receptors have been implicated in schizophrenia (Kerwin et al 1990;Breese et al 1995) and are believed to contribute to the disease but the majority of evidence emphasizes the critical role of NMDA receptors in schizophrenia.…”

Section: Glutamate and Nmda Receptor Dysfunction In Schizophreniamentioning

confidence: 99%

“…Glutamatergic neurons then project to PFC pyramidal neurons and increase the excitatory firing in the PFC (Moghaddam et al 1997;Vinson and Conn 2012 (Lewis et al 2005). These PV+ interneurons may be particularly vulnerable to glutamate dysfunction for several reasons (Lewis and Moghaddam 2006). First, these cells receive more excitatory inputs from pyramidal neurons than other GABA subtypes in the prefrontal cortex (PFC) and hippocampus (Gulyás et al 1999;Melchitzky and Lewis 2003).…”

Section: Nmda Receptor Hypofunction As a Model Of Schizophreniamentioning

confidence: 99%

“…For example, the R1 subunit of NMDA receptors is expressed in more PV+ than other interneurons (Huntley et al 1997;González-Albo et al 2001). Lastly, the activation of PV+ interneurons may be highly dependent upon glutamate receptor activation, resulting in their high sensitivity and vulnerability to NMDA receptor antagonism (Lewis and Moghaddam 2006). NMDA receptor antagonism reduces PV mRNA expression levels by up to 25% in the PFC in rodents without changing neuron density, suggesting these neurons have the capacity to alter PV+ interneuron translational processes (Cochran et al 2003).…”

Section: Nmda Receptor Hypofunction As a Model Of Schizophreniamentioning

confidence: 99%

“…In humans, working memory is dependent upon the dlPFC and functional alterations in this region are observed in patients with schizophrenia (Lewis and Moghaddam 2006).…”

Section: Trial-unique Delayed Nonmatching-to-location Taskmentioning

confidence: 99%

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MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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The cognitive symptoms observed in schizophrenia are highly prevalent and predictive of patient functional outcome but are not usually alleviated by conventional antipsychotics. In a recent pilot study, sodium nitroprusside (SNP), a nitric oxide donor, was identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients.Adjunctive SNP has also been reported to decrease the positive and negative symptoms experienced by patients for weeks following a single administration. The mechanisms underlying these changes and the areas of cognition affected remain largely unknown.Therefore, it is of interest to examine the effects of SNP using a rodent model of schizophrenia that has demonstrated predictive validity. The aim of the present experiment was to explore the effects of SNP on the acute MK-801 rodent model of schizophrenia using a highly translatable task in order to establish its validity. Working memory and pattern separation were measured using the trial-unique, delayed nonmatching-to-location (TUNL) task in touchscreen-equipped operant conditioning chambers. Acute MK-801 administration 25 minutes prior to task initiation impaired both areas of cognition. When SNP and MK-801 were administered within 5 minutes of each other, no interaction was observed. Interestingly, SNP improved performance on trials with difficult to discriminate patterns (p=0.058). Previous rodent studies using the ketamine model of schizophrenia and the novel object preference task observed a preventative effect of SNP administration. When we administered SNP nearly 4 hours prior to MK-801, no cognitive improvements were observed. Our results suggest that SNP may have intrinsic cognitive enhancing properties but is not capable of reducing MK-801-induced working memory and pattern separation impairments in the TUNL task. This study failed to mirror the results of the human pilot study that observed improved working memory following SNP administration.iii Further, it did not replicate previous animal studies using ketamine. Ultimately, the findings suggest that the effects of MK-801 in the TUNL task may not hold the predictive validity needed for its use in the study of SNP. In order to advance the understanding of SNP, future studies should investigate other translatable paradigms to establish validity. iv ACKNOWLDGEMENTSFirst and foremost, I would like to thank my supervisor Dr. John Howland, for his guidance and encouragement over the past three years. He believed in my abilities before I had proven them to myself and pushed me to be the best scientist and student I could be. John has provided me with countless opportunities to grow as a researcher and selflessly helped me make decisions about my future. I would not be where I am today without him and will always be grateful to have had such an incredible mentor in my life.I would like to thank my committee members, Dr.

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Section: The Measurement and Treatment Research To Improve Cognition mentioning

confidence: 99%

Section: Glutamate and Nmda Receptor Dysfunction In Schizophreniamentioning

confidence: 99%

Section: Nmda Receptor Hypofunction As a Model Of Schizophreniamentioning

confidence: 99%

Section: Nmda Receptor Hypofunction As a Model Of Schizophreniamentioning

confidence: 99%

“…In humans, working memory is dependent upon the dlPFC and functional alterations in this region are observed in patients with schizophrenia (Lewis and Moghaddam 2006).…”

Section: Trial-unique Delayed Nonmatching-to-location Taskmentioning

confidence: 99%

See 3 more Smart Citations

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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Short-term Effects of Antipsychotic Treatment on Cerebral Function in Drug-Naive First-Episode Schizophrenia Revealed by “Resting State” Functional Magnetic Resonance Imaging

Lui¹,

Li²,

Deng³

et al. 2010

Arch Gen Psychiatry

337

260

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Elevated Prefrontal Cortex γ-Aminobutyric Acid and Glutamate-Glutamine Levels in Schizophrenia Measured In Vivo With Proton Magnetic Resonance Spectroscopy

Kegeles

Mao²,

Stanford³

et al. 2012

Arch Gen Psychiatry

269

151

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To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies.

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Cognitive Dysfunction in Schizophrenia

Cited by 365 publications

References 40 publications

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

Short-term Effects of Antipsychotic Treatment on Cerebral Function in Drug-Naive First-Episode Schizophrenia Revealed by “Resting State” Functional Magnetic Resonance Imaging

Elevated Prefrontal Cortex γ-Aminobutyric Acid and Glutamate-Glutamine Levels in Schizophrenia Measured In Vivo With Proton Magnetic Resonance Spectroscopy

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