Hyperactive mice show elevated D2High receptors, a model for schizophrenia: Calcium/calmodulin-dependent kinase II alpha knockouts

• Published in: Synapse (New York, N.Y.) Vol. 64; no. 10; pp. 794 - 800
• Main Authors: Novak, Gabriela, Seeman, Philip
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2010
• Subjects: AMPA; animal model; Animal models; Ca super(2+)/calmodulin-dependent protein kinase II; Calcium; CAMK2B; CaMKII; Cortex (frontal); dopamine (DA); Dopamine D2 receptors; Enzymes; Mental disorders; mRNA; Neostriatum; Neuroleptics; NMDA; Schizophrenia; sensitization; striatum; synapse; Synapses
• ISSN: 0887-4476; 1098-2396; 1098-2396
• DOI: 10.1002/syn.20786

The cerebral frontal cortex of patients who had schizophrenia shows elevated levels of RNA for calcium/calmodulin‐dependent protein kinase II beta (CaMKIIβ). 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 (D2High), the major target for antipsychotic medication. The present study was done, therefore, to examine whether an alteration in the levels of CaMKIIβ could lead to altered levels of D2High receptors. We found that the CaMKII inhibitor, KN‐93, markedly reduced D2High states in rat striatum. In addition, we studied heterozygous CaMKIIα knock‐out mice that show features analogous to schizophrenia. The striata of these mice revealed a 2.8‐fold increase in D2High receptors. In frontal cortex of the heterozygous CaMKIIα knock‐out mice, CaMKIIα mRNA levels were reduced by 50%, while CaMKIIβ mRNA levels were unaltered. In striatum, CaMKIIβ mRNA levels were increased by 29%, suggesting the presence of a new CaMKIIβ regulatory pathway not previously described. The elevated levels of CaMKIIβ mRNA in the striatum suggest that this enzyme may increase D2High in animals and possibly in schizophrenia itself. Synapse 64:794–800, 2010. © 2010 Wiley‐Liss, Inc.