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 activity-dependent plasticity in central neurons. To examine in vivo the implication of CaMKII activity in synaptic plasticity, we used an animal model characterized by developmentally induced targeted neuronal ablation within the cortex and the hippocampus, and showing, at presynaptic level, molecular alterations leading to facilitation of glutamate release in hippocampal synapses (methylazoxymethanol-treated rats, MAM-rats). We report here that at the postsynaptic side, the activity of CaMKII is markedly decreased in MAM-rats 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 unchanged in MAM-rats. In addition, the decreased activity is not due to inhibition by autophosphorylation in specific sites within the calmodulin-binding domain, as preincubation with purified phosphatases 1 and 2A failed to restore CaMKII activity in PSD of MAM-rats. The CaMKII-dependent phosphorylation 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-phosphorylation experiments. In addition, a treatment able to restore long-term potentiation (LTP) in hippocampal slices from MAM-rats, e.g. exposure to D-serine, is able to restore CaMKII activity to the control value.
Caputi
A
A
Institute of Pharmacological Sciences, University of Milano, Italy.
Gardoni
F
F
Cimino
M
M
Pastorino
L
L
Cattabeni
F
F
Di Luca
M
M
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002273:Carcinogens; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006624:Hippocampus / Q000166:cytology* / Q000201:enzymology; D017403:In Situ Hybridization; D017774:Long-Term Potentiation / Q000502:physiology*; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology; D009474:Neurons / Q000737:chemistry / Q000201:enzymology; D009924:Organ Culture Techniques; D010766:Phosphorylation; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013569:Synapses / Q000737:chemistry / Q000201:enzymology; D013912:Threonine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism