Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning.
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.
Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, 1051 Riverside Drive, New York, New York 10032, USA.
Christoph
C
Kellendonk
Eleanor H
EH
Simpson
H Jonathan
HJ
Polan
Gaël
G
Malleret
Svetlana
S
Vronskaya
Vanessa
V
Winiger
Holly
H
Moore
Eric R
ER
Kandel
D000262:Adenylyl Cyclases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology; D003342:Corpus Striatum / Q000378:metabolism*; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000633:toxicity; D017397:Prefrontal Cortex / Q000002:abnormalities* / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology; D011485:Protein Binding / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011869:Radioligand Assay / Q000379:methods; D011930:Reaction Time / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D013134:Spiperone / Q000493:pharmacokinetics; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D002247:Carbon Isotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018690:Excitatory Amino Acid Agonists; D016760:Proto-Oncogene Proteins c-fos; D017448:Receptors, Dopamine D2; D014316:Tritium; D013134:Spiperone; D016202:N-Methylaspartate; D003847:Deoxyglucose; D000262:Adenylyl Cyclases; D005947:Glucose; D004318:Doxycycline