title: Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior.
abstract: Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor (Drd1a)+ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P, and dynorphin expression is progressively lost, whereas D2 dopamine receptor (Drd2) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electrographically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in the oral behaviors of sifting and chewing. In line with the limbic seizure profile, cell loss, astrogliosis, microgliosis, and down-regulated dynorphin expression were seen in the hippocampal dentate gyrus. This study specifically implicates Drd1a+ cell loss with tail suspension hindlimb dystonia, hyperactivity, and abnormal oral function. The latter may relate to the speech and swallowing disturbances and the classic sign of tongue-protrusion motor impersistence observed in Huntington's disease. In addition, the findings of this study support the notion that Drd1a and Drd2 are segregated on striatal projection neurons.
authors.affiliation: Howard Florey Institute, University of Melbourne, Melbourne 3010, Australia.
authors.forename: Ilse
authors.initials: I
authors.lastname: Gantois
authors.forename: Ke
authors.initials: K
authors.lastname: Fang
authors.forename: Luning
authors.initials: L
authors.lastname: Jiang
authors.forename: Daniela
authors.initials: D
authors.lastname: Babovic
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ferreri
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Teper
authors.forename: Bianca
authors.initials: B
authors.lastname: Jupp
authors.forename: Jenna
authors.initials: J
authors.lastname: Ziebell
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Morganti-Kossmann
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: Rachel
authors.initials: R
authors.lastname: Nally
authors.forename: Günter
authors.initials: G
authors.lastname: Schütz
authors.forename: John
authors.initials: J
authors.lastname: Waddington
authors.forename: Gary F
authors.initials: GF
authors.lastname: Egan
authors.forename: John
authors.initials: J
authors.lastname: Drago
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015536:Down-Regulation; D004421:Dystonia / Q000473:pathology*; D004569:Electroencephalography; D005260:Female; D006816:Huntington Disease / Q000378:metabolism; D006948:Hyperkinesis / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008953:Models, Anatomic; D011954:Receptors, Dopamine / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics* / Q000502:physiology*; D012640:Seizures / Q000473:pathology*
chemical_list: D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1