Molecular and Cellular Mechanisms Underlying Spatial Learning

Understanding the molecular and cellular mechanisms underlying learning and memory is one of the most exciting topics in the field of Neuroscience. Learning is thought to occur through activity-dependent synaptic modification in the neuronal network. The hippocampus, is an excellent structure to study synaptic plasticity and learning, because of its anatomy and network. Most of the studies in this thesis were performed on the hippocampus to unravel the molecular and cellular mechanisms underlying spatial learning. Molecular and cellular studies of mechanisms underlying mammalian learning and memory have focused almost exclusively on postsynaptic function. However, in chapter 2 we reveal a presynaptic mechanism that modulates learning and synaptic plasticity in mice. Using transgenic mice expressing a constitutively active form of H-ras (H- rasG12V), we studied the H-Ras/ERK/Syn I pathway and showed that in these mice ERK-dependent phosphorylation of synansin I is increased and causes several presynaptic changes. Calcium-calmodulin dependent protein kinase II (CaMKII) is a protein kinase, which detects Ca2+ signals and can phosphorylate many target proteins as well as itself. This auto-phosphorylation is critical for its role in LTP and learning. However, in chapter 3 we show that although CaMKII is required for normal presynaptic function, its ability to phospho

Rescue of neurological deficits in a mouse model for Angelman Syndrome by reduction of αCaMKII inhibitory phosphorylation

Angelman Syndrome (AS) is a severe neurological disorder characterized by mental retardation, motor dysfunction and epilepsy. We now show that the molecular and cellular deficits of an AS mouse model can be rescued by introducing an additional mutation at the inhibitory phosphorylation site of αCaMKII. Moreover, these double mutants do no longer show the behavioral deficits seen in AS mice, suggesting that these deficits are the direct result of increased αCaMKII inhibitory phosphorylation