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: Yasushi Yabuki, Norifumi Shioda, Tomomi Maeda, Sachiko Hiraide, Hiroko Togashi, Kohji Fukunaga
• Journal: Brain research (Brain Res) Vol. 1557 Pg. 90-100 (Apr 04 2014) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 24561222 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Enzyme Reactivators
• Receptors, AMPA
• Receptors, Dopamine D1
• Receptors, Dopamine D2
• Methylphenidate
• Protein Kinase C
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Extracellular Signal-Regulated MAP Kinases
• glutamate receptor ionotropic, AMPA 1

Topics

• Animals
• Attention (drug effects)
• Attention Deficit Disorder with Hyperactivity (complications, drug therapy, enzymology)
• CA1 Region, Hippocampal (drug effects, enzymology)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Cognition Disorders (drug therapy, enzymology, etiology)
• Disease Models, Animal
• Enzyme Reactivators (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Male
• Maze Learning (drug effects)
• Methylphenidate (pharmacology)
• Neuropsychological Tests
• Prefrontal Cortex (drug effects, enzymology)
• Protein Kinase C (metabolism)
• Rats
• Rats, Inbred WKY
• Receptors, AMPA (metabolism)
• Receptors, Dopamine D1 (metabolism)
• Receptors, Dopamine D2 (metabolism)
• Recognition, Psychology (drug effects)