title: Motor and behavioral phenotype in conditional mutants with targeted ablation of cortical D1 dopamine receptor-expressing cells.
abstract: D1-dopamine receptors (Drd1a) are highly expressed in the deep layers of the cerebral cortex and the striatum. A number of human diseases such as Huntington disease and schizophrenia are known to have cortical pathology involving dopamine receptor expressing neurons. To illuminate their functional role, we exploited a Cre/Lox molecular paradigm to generate Emx-1(tox) MUT mice, a transgenic line in which cortical Drd1a-expressing pyramidal neurons were selectively ablated. Emx-1(tox) MUT mice displayed prominent forelimb dystonia, hyperkinesia, ataxia on rotarod testing, heightened anxiety-like behavior, and age-dependent abnormalities in a test of social interaction. The latter occurred in the context of normal working memory on testing in the Y-maze and for novel object recognition. Some motor and behavioral abnormalities in Emx-1(tox) MUT mice overlapped with those in CamKIIα(tox) MUT transgenic mice, a line in which both striatal and cortical Drd1a-expressing cells were ablated. Although Emx-1(tox) MUT mice had normal striatal anatomy, both Emx-1(tox) MUT and CamKIIα(tox) MUT mice displayed selective neuronal loss in cortical layers V and VI. This study shows that loss of cortical Drd1a-expressing cells is sufficient to produce deficits in multiple motor and behavioral domains, independent of striatal mechanisms. Primary cortical changes in the D1 dopamine receptor compartment are therefore likely to model a number of core clinical features in disorders such as Huntington disease and schizophrenia.
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia; St Vincent's Hospital, Melbourne, Victoria, Australia.
authors: Luning
authors: L
authors: Jiang
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia; Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: Claire
authors: C
authors: O'Leary
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors: Hyun Ah
authors: HA
authors: Kim
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors: Clare L
authors: CL
authors: Parish
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors: Jim
authors: J
authors: Massalas
authors: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: John L
authors: JL
authors: Waddington
authors: Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
authors: Michelle E
authors: ME
authors: Ehrlich
authors: Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Günter
authors: G
authors: Schütz
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors: Ilse
authors: I
authors: Gantois
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors: Andrew J
authors: AJ
authors: Lawrence
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia; St Vincent's Hospital, Melbourne, Victoria, Australia. Electronic address: john.drago@florey.edu.au.
authors: John
authors: J
authors: Drago
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000502:physiology; D002540:Cerebral Cortex / Q000502:physiology*; D005260:Female; D005684:Gait / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D017966:Pyramidal Cells / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology*; D012919:Social Behavior; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018398:Homeodomain Proteins; D017447:Receptors, Dopamine D1; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins
keywords: D1-dopamine receptor; Dystonia; Huntington disease; Schizophrenia; Targeted cell deletion