CaMKII-dependent phosphorylation of NR2A and NR2B is decreased in animals characterized by hippocampal damage and impaired LTP

The calcium-calmodulin-dependent protein kinase II (CaMKII) subserves activ ity-dependent plasticity in central neurons. To examine in vivo the implica tion of CaMKII activity in synaptic plasticity, we used an animal model cha racterized by developmentally induced targeted neuronal ablation within the cortex and the hippocampus, and showing, at presynaptic level, molecular a lterations leading to facilitation of glutamate release in hippocampal syna pses (methylazoxymethanol-treated rats, MAM-rats). We report here that at t he postsynaptic side, the activity of CaMKII is markedly decreased in MAM-r ats when compared to controls, although the concentration of the enzyme in Post Synaptic Density (PSD) is not altered. This effect is confined to PSD- associated CaMKII, as enzyme activity tested in the soluble fraction is unc hanged in MAM-rats, In addition, the decreased activity is not due to inhib ition by autophosphorylation in specific sites within the calmodulin-bindin g domain, as preincubation with purified phosphatases 1 and 2A failed to re store CaMKII activity in PSD of MAM-rats. The CaMKII-dependent phosphorylat ion of NR2A/B subunits of NMDA receptor is lower in MAM-rats when compared to controls (51.77 +/- 7.39% of controls level), as revealed in back-phosph orylation experiments. In addition, a treatment able to restore long-term p otentiation (LTP) in hippocampal slices from MAM-rats, e.g. exposure to D-s erine, is able to restore CaMKII activity to the control value.