Peters, Marco; (2003) The calcium/calmodulin regulated kinase cascade in learning and memory. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

An important goal in modern neuroscience is the identification of molecular mechanisms that contribute to long-term memory (LTM). The formation of LTM requires activation of the transcription factor cAMP responsive element binding protein (CREB) and de novo synthesis of proteins. Although a large body of research has established a function for CREB-dependent transcription in learning and memory, little is known as to how CREB is activated. One of the suggested activation pathways is the calcium-calmodulin (CaM) regulated kinase cascade. An essential component of the CaM kinase cascade is CaM kinase kinase (3 (CaMKK). To test the function of CaMKK in learning and memory, the Camkk2 gene was targeted in mice. Using the Cre-loxP system, mice with a global deletion of CaMKK (Camkk2 null) and mice with a floxed (flanked by loxP-sites) allele of Camkk2 (Camkk2 floxed) were generated. Camkk2 null mutant mice were viable, fertile, and they showed no obvious abnormalities. The loss of CaMKK did not affect motor learning as tested on the Rota- rod. Furthermore, no gross morphological abnormalities could be detected at the light microscopic level. Behavioural studies revealed that the null mutants had a specific LTM deficit in the social transmission of food preferences task, suggesting that hippocampal function was affected by the loss of CaMKK. However, in contrast to CREB, CaMKK signalling was not required for hippocampus dependent LTM formation of contextual fear. Surprisingly, male but not female mutants were impaired in spatial memory formation in the Morris water maze. The results of this study suggest that CREB is differentially activated for the formation of specific types of hippocampal memories. Furthermore, an important dichotomy of the signalling mechanisms employed for spatial LTM formation by the genders was revealed. Whereas male mice require CaMKK[beta] for spatial memory formation, female mice can use other signalling pathways instead.

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