Cited by 521Neurotransmitter Receptor Influence on BehaviorSchizophrenia research and treatmentNeuroscience and Neuropharmacology Research

Transient and Selective Overexpression of Dopamine D2 Receptors in the Striatum Causes Persistent Abnormalities in Prefrontal Cortex Functioning

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Kellendonk, Christoph, Simpson, Eleanor H., Polan, H. Jonathan, Malleret, Gaël, Vronskaya, Svetlana, Winiger, Vanessa, Moore, Holly, Kandel, Eric R.·2006·Neuron

Abstract

Increased activity of D2 receptors (D2Rs) in the striatum has been linked to the pathophysiology of schizophrenia. To determine directly the behavioral and physiological consequences of increased D2R function in the striatum, we generated mice with reversibly increased levels of D2Rs restricted to the striatum. D2 transgenic mice exhibit selective cognitive impairments in working memory tasks and behavioral flexibility without more general cognitive deficits. The deficit in the working memory task persists even after the transgene has been switched off, indicating that it results not from continued overexpression of D2Rs but from excess expression during development. To determine the effects that may mediate the observed cognitive deficits, we analyzed the prefrontal cortex, the brain structure mainly associated with working memory. We found that D2R overexpression in the striatum impacts dopamine levels, rates of dopamine turnover, and activation of D1 receptors in the prefrontal cortex, measures that are critical for working memory.

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Crossref · 10.1016/j.neuron.2006.01.023

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Authors
Kellendonk, C., Simpson, E. H., Polan, H. J., Malleret, G., Vronskaya, S., Winiger, V., Moore, H., & Kandel, E. R.
Affiliations
  • Columbia University (US)
  • Cornell University (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Simpson, Eleanor H.
  • Kandel, Eric R.
Venue
Neuron
Publisher
Elsevier BV
Published
2006-02
Volume
49
Issue
4
Pages
603-615
ISSN
0896-6273 (ISSN-L)
OpenAlex
W2059669521
Cited by
520
References
69
Citations by year
2026: 5 · 2025: 11 · 2024: 12 · 2023: 10 · 2022: 25 · 2021: 17 · 2020: 19 · 2019: 18 · 2018: 32 · 2017: 17 · 2016: 24 · 2015: 31 · 2014: 37 · 2013: 36 · 2012: 38
FWCI
14.65
Type
journal article
Language
en
Open access
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • Deutsche Forschungsgemeinschaft
  • National Institutes of Health (5p50mh066171-05)
  • National Institute of Mental Health (P50-MH066171)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
dopamine D2 receptor, striatum, schizophrenia, working memory, behavioral flexibility, prefrontal cortex, dopamine D1 receptor, dopamine turnover, transgenic mice, cognitive impairment
MeSH terms
Adenylyl Cyclases, Analysis of Variance, Animals, Behavior, Animal, Carbon Isotopes, Cognition Disorders, Corpus Striatum, Deoxyglucose, Disease Models, Animal, Dose-Response Relationship, Drug, Doxycycline, Glucose, Humans, Immunohistochemistry, Male, Memory, Short-Term, Mice, Inbred C57BL, Mice, Transgenic, Protein Binding, Radioligand Assay, Reaction Time, Spiperone, Time Factors, Tritium, Gene Expression, N-Methylaspartate, Proto-Oncogene Proteins c-fos, Prefrontal Cortex, In Situ Hybridization, Receptors, Dopamine D2, Dopamine Agonists, Dopamine Antagonists, Excitatory Amino Acid Agonists, Mice

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