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Elevated Plus Maze for Mice
Published on: December 22, 2008
Hyperactive mice show elevated D2(High) receptors, a model for schizophrenia: Calcium/calmodulin-dependent kinase II
Gabriela Novak1, Philip Seeman
1Department of Pharmacology, Medical Science Building, Room 4345, University of Toronto, Toronto, Ontario, Canada M5S 1A8. gabriela.novak@utoronto.ca
Abstract:
The cerebral frontal cortex of patients who had schizophrenia shows elevated levels of RNA for calcium/calmodulin-dependent protein kinase II beta (CaMKIIbeta). In addition, recent research shows that animal models for schizophrenia, such as amphetamine-sensitized rats, consistently show elevated levels of D2 receptors in their high-affinity state (D2(High)), the major target for antipsychotic medication. The present study was done, therefore, to examine whether an alteration in the levels of CaMKIIbeta could lead to altered levels of D2(High) receptors. We found that the CaMKII inhibitor, KN-93, markedly reduced D2(High) states in rat striatum. In addition, we studied heterozygous CaMKIIalpha knock-out mice that show features analogous to schizophrenia. The striata of these mice revealed a 2.8-fold increase in D2(High) receptors. In frontal cortex of the heterozygous CaMKIIalpha knock-out mice, CaMKIIalpha mRNA levels were reduced by 50%, while CaMKIIbeta mRNA levels were unaltered. In striatum, CaMKIIbeta mRNA levels were increased by 29%, suggesting the presence of a new CaMKIIbeta regulatory pathway not previously described. The elevated levels of CaMKIIbeta mRNA in the striatum suggest that this enzyme may increase D2(High) in animals and possibly in schizophrenia itself.
Insights
Altered calcium/calmodulin-dependent protein kinase II beta (CaMKIIbeta) levels may increase D2(High) receptors, a key target for antipsychotics. This finding offers new insights into schizophrenia's molecular mechanisms.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Schizophrenia is linked to elevated CaMKIIbeta RNA in the frontal cortex.
- Animal models of schizophrenia exhibit increased D2(High) receptors, a target for antipsychotics.
Purpose of the Study:
- To investigate the relationship between CaMKIIbeta levels and D2(High) receptor expression.
- To explore the potential role of CaMKIIbeta in schizophrenia.
Main Methods:
- Administered CaMKII inhibitor KN-93 to rats and measured D2(High) receptor levels.
- Studied heterozygous CaMKIIalpha knock-out mice exhibiting schizophrenia-like features, analyzing CaMKII and D2(High) receptor levels in brain regions.
Main Results:
- KN-93 significantly reduced D2(High) receptor levels in rat striatum.
- CaMKIIalpha knock-out mice showed a 2.8-fold increase in striatal D2(High) receptors.
- Striatal CaMKIIbeta mRNA levels increased by 29% in knock-out mice, suggesting a novel regulatory pathway.
Conclusions:
- CaMKIIbeta may play a role in elevating D2(High) receptors in animal models and potentially in schizophrenia.
- Findings suggest CaMKIIbeta as a potential therapeutic target for schizophrenia.
