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 phosphorylate itself, or other proteins does not appear to be necessary for its presynaptic role. This suggests that CaMKII plays a structural (non-enzymatic) role and may explain why this kinase is so abundant. The phosphorylation of CaMKII appears to be deregulated in Angelman syndrome, a severe neurological disorder. Specifically, phosphorylation at CaMKII-Thr305/Thr306 appears to be increased which results in self-inhibition of CaMKII. However to what extend the neurological deficits can be attributed to the increased self- inhibition was not known. In chapter 4 we provide strong evidence that the major neurological symptoms are directly attributable by this increased self-inhibited form of CaMKII. In chapter 5 we studied one of the most common single-gene disorders affecting cognitive function in human, neurofibromatosis type 1 (NF1). We investigated the importance of the alternatively spliced exon 9a in NF1 function. This exon is not a part of GAP domain and its function is unknown. We created a mouse lacking the NF1-Ex9a isoform and showed that these mice have hippocampal learning deficits and impaired LTP. It does appears that this exon is critical for the role of NF1 in synaptic function and this suggest that NF1 may play an additional role besides Ras regulation. The hippocampus is not the only structure involved in spatial learning. Other structures have also been implicated in spatial learning. In chapter 6, we made use of L7-PKCI transgenic mice, which lack parallel fiber-Purkinje cell LTD, to test the involvement of the cerebellum. This study strongly suggested a role for the cerebellum in goal directed behavior.