Implication of CaMKII in a Learning Disorder

Science's STKE  29 Apr 2003:
Vol. 2003, Issue 180, pp. tw168-TW168
DOI: 10.1126/stke.2003.180.tw168

Weeber et al. investigated the biochemical mechanisms underlying deficits in hippocampal long-term potentiation (LTP) in a model of Angelman syndrome and discovered evidence linking this cognitive disorder to dysregulation of calcium/calmodulin-dependent protein kinase II (CaMKII). Angelman syndrome, which is characterized by mental retardation, decreased brain size, predisposition to seizures, and disturbed gait, is associated with a deletion on maternal chromosome 15 that leads to disruption of the Ube3a gene, which encodes E6-AP ubiquitin ligase. A mouse model null for maternal Ube3a recapitulates many features of this disorder and shows deficits in hippocampal LTP. Weeber et al. discovered that LTP in hippocampal slices from Ube3a mutant mice could be rescued by increasing temperature and additional stimulation, whereas calcium (Ca2+)-dependent, N-methyl-D-aspartate receptor-independent LTP could not. The authors used Western analysis to determine the concentrations and phosphorylation status of hippocampal Ca2+-regulated protein kinases. Protein kinase C (PKC), protein kinase A (PKA), p42 and p44 extracellular signal-regulated kinase (ERK), and CaMKII concentrations were unchanged from those of controls, as was PKC, PKA, and ERK phosphorylation status. However, phosphorylation of CaMKII was increased, which acted to inhibit its activity. There was reduced activation of CaMKII from Ube3a mice after in vitro stimulation with Ca2+ and calmodulin, and less CaMKII was associated with isolated postsynaptic densities. Decreased activity of the CaMKII phosphatases, PPI and PP2A, suggested that increased phosphorylation of CaMKII was secondary to a reduction in phosphatase activity. These data suggest that dysregulation of CaMKII phosphorylation (and thereby CaMKII activity) likely underlies the deficits in LTP in Ube3a mice and perhaps the cognitive deficits in Angelman syndrome.

E. J. Weeber, Y.-H. Jiang, Y. Elgersma, A. W. Varga, Y. Carasquillo, S. E. Brown, J. M. Christian, B. Mirnikjoo, A. Silva, A. L. Beaudet, J. D. Sweatt, Derangement of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J. Neurosci. 23, 2634-2644 (2003). [Abstract] [Full Text]