Aberrant CaMKII activity in the medial prefrontal cortex is associated with cognitive dysfunction in ADHD model rats

Yasushi Yabuki, Norifumi Shioda, Tomomi Maeda, Sachiko Hiraide, Hiroko Togashi, Kohji Fukunaga

Research output: Contribution to journalArticle

20 Citations (Scopus)

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: 1 mg/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, Ca2+/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). Ca2+-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 (1 mg/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.

Original languageEnglish
Pages (from-to)90-100
Number of pages11
JournalBrain research
Volume1557
DOIs
Publication statusPublished - 2014 Apr 4

Keywords

  • Attention-deficit/hyperactivity disorder
  • Cognitive dysfunction
  • Dopamine D2 receptor
  • Stroke-prone spontaneously hypertensive rats

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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