Abstract
Calcium-calmodulin dependent protein kinase IV (CaMKIV) is a protein kinase that activates the transcription factor CREB, the cyclic AMP-response element binding protein. CREB is a key transcription factor in synaptic plasticity and memory consolidation. To elucidate the behavioral effects of CaMKIV deficiency, we subjected CaMKIV knockout (CaMKIV KO) mice to a battery of behavioral tests. CaMKIV KO had no significant effects on locomotor activity, motor coordination, social interaction, pain sensitivity, prepulse inhibition, attention, or depression-like behavior. Consistent with previous reports, CaMKIV KO mice exhibited impaired retention in a fear conditioning test 28 days after training. In contrast, however, CaMKIV KO mice did not show any testing performance deficits in passive avoidance, one of the most commonly used fear memory paradigms, 28 days after training, suggesting that remote fear memory is intact. CaMKIV KO mice exhibited intact spatial reference memory learning in the Barnes circular maze, and normal spatial working memory in an eight-arm radial maze. CaMKIV KO mice also showed mildly decreased anxiety-like behavior, suggesting that CaMKIV is involved in regulating emotional behavior. These findings indicate that CaMKIV might not be essential for fear memory or spatial memory, although it is possible that the activities of other neural mechanisms or signaling pathways compensate for the CaMKIV deficiency.
Highlights
Establishing animal models of psychiatric disorders using genetically engineered mice is essential for investigating the pathogenesis/pathophysiology and treatment of these disorders [1,2,3]
Generation and Characterization of calmodulin dependent protein kinase IV (CaMKIV) KO Mice To disrupt CaMKIV, the exon containing an initiation codon for CaMKIVa was replaced with a neomycin resistance cassette (Fig. 1A)
In situ hybridization analysis with a radioactive oligonucleotide probe revealed that CaMKIV mRNA was completely attenuated in brains of CaMKIV null mice and the expression level was decreased by about 50% in brains of heterozygous mice (Fig. 1C)
Summary
Establishing animal models of psychiatric disorders using genetically engineered mice is essential for investigating the pathogenesis/pathophysiology and treatment of these disorders [1,2,3]. We and others have identified a potential schizophrenia and bipolar disorder susceptibility gene, the PPP3CC gene, which encodes the calcineurin gamma subunit [6,7,8,9,10,11]. These studies demonstrate the usefulness of subjecting genetically engineered mice to a comprehensive battery of behavioral tests to establish a mouse model of human psychiatric disorders. CaMKIV phosphorylates CREB and the phosphorylation is terminated by calcineurin, possibly through direct CREB dephosphorylation or through activation of the downstream protein phosphatase 1 [19]
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