Forebrain overexpression of CK1delta leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD.
Dopamine neurotransmission controls motor and perseverative behavior, is mediated by protein phosphorylation, and may be perturbed in disorders of attention and hyperactivity. To assess the role of casein kinase I (CK1) in the regulation of dopamine signaling, we generated a genetically modified mouse line that overexpresses CK1delta (CK1delta OE) specifically in the forebrain. Overexpression was confirmed both at the mRNA and at the protein levels. Under basal conditions, CK1delta OE mice exhibited horizontal and vertical hyperactivity, reduced anxiety, and nesting behavior deficiencies. The CK1delta OE mice also presented paradoxical responses to dopamine receptor stimulation, showing hypoactivity following injection of d-amphetamine or methylphenidate, indicating that CK1 activity has a profound effect on dopamine signaling in vivo. Interestingly, CK1delta overexpression led to significantly reduced D1R and D2R dopamine receptor levels. All together, under basal conditions and in response to drug stimulation, the behavioral phenotype of CK1delta OE mice is reminiscent of the symptoms and drug responses observed in attention-deficit/hyperactivity disorder and therefore the CK1delta OE mice appear to be a model for this disorder.
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
Mingming
M
Zhou
Heike
H
Rebholz
Christine
C
Brocia
Jennifer L
JL
Warner-Schmidt
Allen A
AA
Fienberg
Angus C
AC
Nairn
Paul
P
Greengard
Marc
M
Flajolet
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000201:enzymology / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D048148:Casein Kinase Idelta / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015536:Down-Regulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008124:Locomotion; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D016548:Prosencephalon / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D008774:Methylphenidate; D016291:Dizocilpine Maleate; D000661:Amphetamine; D048148:Casein Kinase Idelta