TY - JOUR
T1 - Transient and selective overexpression of D2 receptors in the striatum causes persistent deficits in conditional associative learning
AU - Bach, Mary Elizabeth
AU - Simpson, Eleanor H.
AU - Kahn, Lora
AU - Marshall, John J.
AU - Kandel, Eric R.
AU - Kellendonk, Christoph
PY - 2008/10/14
Y1 - 2008/10/14
N2 - Cognitive deficits in schizophrenia are thought to derive from a hypofunction of the prefrontal cortex (PFC), but the origin of the hypofunction is unclear. To explore the nature of this deficit, we genetically modified mice to model the increase in striatal dopamine D2 receptors (D 2Rs) observed in patients with schizophrenia. Previously, we reported deficits in spatial working memory tasks in these mice, congruent with the working memory deficits observed in schizophrenia. However, patients with schizophrenia suffer from deficits in many executive functions, including associative learning, planning, problem solving, and nonspatial working memory. We therefore developed operant tasks to assay two executive functions, conditional associative learning (CAL) and nonspatial working memory. Striatal D2R-overexpressing mice show a deficit in CAL because of perseverative behavior, caused by interference from the previous trial. D 2R up-regulation during development was sufficient to cause this deficit, because switching off the transgene in adulthood did not rescue the phenotype. We validated prefrontal dependency of CAL by using neurotoxic lesions. Lesions of the medial PFC including the anterior cingulate, infralimbic, and prelimbic cortices impair CAL because of increased interference from previously rewarded trials, exactly as observed in D2R transgenic mice. In contrast, lesions restricted to the infralimbic and prelimbic cortices have no effect on CAL but impair performance in the nonspatial working memory task. These assays not only give us insight into how excess striatal D2Rs affect cognition but also provide tools for studying cognitive endophenotypes in mice.
AB - Cognitive deficits in schizophrenia are thought to derive from a hypofunction of the prefrontal cortex (PFC), but the origin of the hypofunction is unclear. To explore the nature of this deficit, we genetically modified mice to model the increase in striatal dopamine D2 receptors (D 2Rs) observed in patients with schizophrenia. Previously, we reported deficits in spatial working memory tasks in these mice, congruent with the working memory deficits observed in schizophrenia. However, patients with schizophrenia suffer from deficits in many executive functions, including associative learning, planning, problem solving, and nonspatial working memory. We therefore developed operant tasks to assay two executive functions, conditional associative learning (CAL) and nonspatial working memory. Striatal D2R-overexpressing mice show a deficit in CAL because of perseverative behavior, caused by interference from the previous trial. D 2R up-regulation during development was sufficient to cause this deficit, because switching off the transgene in adulthood did not rescue the phenotype. We validated prefrontal dependency of CAL by using neurotoxic lesions. Lesions of the medial PFC including the anterior cingulate, infralimbic, and prelimbic cortices impair CAL because of increased interference from previously rewarded trials, exactly as observed in D2R transgenic mice. In contrast, lesions restricted to the infralimbic and prelimbic cortices have no effect on CAL but impair performance in the nonspatial working memory task. These assays not only give us insight into how excess striatal D2Rs affect cognition but also provide tools for studying cognitive endophenotypes in mice.
KW - Cognitive symptoms
KW - Dopamine D receptors
KW - Genetic mouse models
KW - Prefrontal cortex lesion
KW - Schizophrenia
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U2 - 10.1073/pnas.0807746105
DO - 10.1073/pnas.0807746105
M3 - Article
C2 - 18832466
AN - SCOPUS:57349138282
SN - 0027-8424
VL - 105
SP - 16027
EP - 16032
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 41
ER -