Role of CaMKI in structural plasticity and memory

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Long-term memory is thought to involve changes in the connections (synapses) between neurons. These changes may involve either the rapid modification of existing connections between neurons (e.g., synaptic plasticity) or slower structural changes leading to the addition/elimination of synapses and modulation of axonal and dendritic growth (structural plasticity). While previous studies have focused on the role of axonal and dendritic growth in the formation of neural circuits in the developing brain, less attention has been paid to how these forms of structural plasticity contribute to memory formation in the adult brain. Recently, two isoforms of the calcium/calmodulin kinase I (CaMKI-gamma and CaMKI-alpha) have been shown to play complementary roles dendritogenesis and axonogenesis in a cell culture system. Here we propose to explore the role of CaMKI-gamma and CaMKI-alpha in memory formation in the adult brain. In preliminary studies we have examined mice with a global deletion of CaMKI-gamma, and found that CaMKI-gamma heterozygous (CaMKI-gamma+/-) mice were impaired in contextual fear conditioning and spatial learning, consistent with the finding that disrupting CaMKI-gamma function disrupts dendritogenesis in cell culture. This raises the possibility that this kinase plays a key role in structural plasticity required for hippocampal memory in the adult brain. However, as in these global knockout mice CaMKI-gamma was constitutively deleted from all cells, it is not possible to tease apart the effects of the deletion on developmental vs. adult plasticity. In order to address this issue, we propose to use a cre-loxP strategy to restrict deletion of CaMKI-gamma and CaMKI-alpha to a) forebrain excitatory circuits (by crossing floxed CaMKI-gamma or -alpha mice with CaMKII-creERT2 mice), and b) adult-generated neurons (by crossing floxed CaMKI-gamma or -alpha mice with nestin-creERT2 mice) in adult mice. By using these different lines of transgenic mice expressing cre-recombinase under different promoters we are able to delete CaMKI-gamma and CaMKI-alpha in a temporally and cell-type specific manner, and explore the contribution of this kinase to structural plasticity and memory in the adult brain.