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.

N‐methyl‐d‐aspartate receptor dysfunction in the prefrontal cortex of stroke‐prone spontaneously hypertensive rat/Ezo as a rat model of attention deficit/hyperactivity disorder

“…Moreover, neither the B max nor K d of [ 3 H]MK‐801 binding in the hippocampus was significantly different between each type of rats, suggesting that NMDA receptor dysfunction in SHRSP/Ezo is PFC‐specific manner. These results are consistent with a recent report that the PFC, but not hippocampus, is likely to be responsible for AD/HD‐related behavioral deficits in SHRSP/Ezo . However, Jansen et al reported that one of the AD/HD animal models, SHR, showed the NMDA receptor subunit dysfunction in the hippocampus.…”

The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation

“…To conclude, not only are these findings reminiscent of a role of CaMKIIα dysfunction in brain disorders such as Angelman syndrome (68), attention deficit hyperactivity disorder (69) and cerebral ischemia (39), they also resonate with the emerging concept that CaMKIIα is altering neuronal physiology and cognition more generally when aberrantly over-activated in the brain. In combination with earlier studies (2, 49), these results establish that distinct endogenous Aβ oligomers activate specific neuronal signaling pathways, and that mapping the specific tau changes induced by each of these Aβ toxins might provide a general template for monitoring AD progression.…”

“…Mouse cortical cultures of neurons were prepared from 14- to 15-d-old embryos as described previously (2, 69, 70) using 5×10 5 cells/dish. After 3 d in vitro (DIV), neurons were treated with 10 μM AraC to inhibit proliferation of non-neuronal cells.…”

Angiotensin II modulates amphetamine‐induced glial and brain vascular responses, and attention deficit via angiotensin type 1 receptor: Evidence from brain regional sensitivity to amphetamine

“…In this brain area, catecholamine neurotransmission is implicated in the coordination and integration of cues, even though they imply less complex behaviors (Arnsten, ; Jones, ). In this sense, attention is required when animals perform spatial recognition of novel environments; thus, behavioral tests evaluating exploration are indicative of PFC functional integrity, among other brain areas, such as HPC and other limbic structures (Dudchenko, ; Lalonde, ; Yabuki et al, ). The Amph‐induced working memory deficit in rodents has been previously related to oligodendrocyte altered morphology in PFC, supporting the coexistence of functional and structural alterations in this brain area after Amph exposure (Yang, Wang, Cheng, & Xu, ).…”