Transient and Selective Overexpression of Dopamine D2 Receptors in the Striatum Causes Persistent Abnormalities in Prefrontal Cortex Functioning
Open accessAbstract
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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Transient overexpression of D2 receptors in the striatum of mice resulted in deficits in prefrontal working memory, resembling some features of human schizophrenia.
“transient overexpression of D2 receptors in the striatum of mice resulted in deficits in prefrontal working memory, resembling some of the features of human schizophrenia [80].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [80]
In genetically engineered mice, 30% of striatal MSNs overexpressed engineered D2 receptors, elevating the D2 receptor level to about 15% higher than normal mice.
“It was found that 30% of striatal MSNs overexpressed these engineered receptors, thereby elevating the D2 receptor level to about 15% higher than that of normal mice.”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [80]
Mice with striatal D2 receptor upregulation have abnormal cognitive phenotypes including working-memory deficits, reversal-learning impairment, and decreased social interactions.
“were shown to have several abnormal cognitive phenotypes, including working-memory deficits, reversal-learning impairment and decreased social interactions.”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [80]
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Self-citation
- 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.
- ORCID
- 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
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2723 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- 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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