title: Aberrant CaMKII activity in the medial prefrontal cortex is associated with cognitive dysfunction in ADHD model rats.
abstract: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurobehavioral disorder accompanied by cognitive and learning deficits, which is prevalent among boys. Juvenile male stroke-prone spontaneously hypertensive rats (SHRSP) exhibit ADHD-like behaviors including cognitive deficits and represent one animal model of ADHD. Here, we define a mechanism underlying cognitive dysfunction observed in SHRSP. Acute methylphenidate (MPH: 1mg/kg, p.o.) administration to SHRSP significantly improved not only inattention in a Y-maze task but also cognitive dysfunction in a novel object recognition test. Interestingly, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity, which is essential for memory and learning acquisition, was excessively elevated in the medial prefrontal cortex (mPFC) but not in the hippocampal CA1 region of SHRSP compared with Wistar-Kyoto (WKY) rats. We also confirmed that elevated CaMKII autophosphorylation in the mPFC causes increased phosphorylation of the CaMKII substrate α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid-type glutamate receptor subunit 1 (GluR1) (Ser-831). Ca(2+)-dependent phosphorylation levels of factors such as extracellular signal-regulated kinase (ERK) and protein kinase C (PKC) were unchanged in the SHRSP mPFC. Also, protein levels of the dopamine D2 receptor (D2R) but not the dopamine D1 receptor (D1R) were increased in the SHRSP mPFC. Acute MPH (1mg/kg, p.o.) administration attenuated aberrant CaMKII activity and increased GluR1 phosphorylation observed in SHRSP. Taken together, we propose that cognitive impairment in SHRSP is associated with aberrant CaMKII activity in the mPFC.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yabuki
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shioda
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences Health Sciences, University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hiraide
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences Health Sciences, University of Hokkaido, Ishikari-Tobetsu, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togashi
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. Electronic address: kfukunaga@m.tohoku.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects; D001289:Attention Deficit Disorder with Hyperactivity / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000201:enzymology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D004195:Disease Models, Animal; D004793:Enzyme Reactivators / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008774:Methylphenidate / Q000494:pharmacology; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D018091:Receptors, AMPA / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004793:Enzyme Reactivators; D048049:Extracellular Signal-Regulated MAP Kinases; D008774:Methylphenidate; D011493:Protein Kinase C; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2
keywords: Attention-deficit/hyperactivity disorder; Ca(2+)/calmodulin-dependent protein kinase II; Cognitive dysfunction; Dopamine D2 receptor; Stroke-prone spontaneously hypertensive rats