| Within the theoretical frame of the Hebbian synapse, by which presynaptic axonal growth may occur to increase the efficiency in firing the postsynaptic cell, and this way subserve learning and memory mechanisms, I have conducted studies aimed at improving our understanding of how axonal growth is regulated. I have done so by focusing on the molecular events orchestrating the expression of an intrinsic determinant of axonal growth: the synaptic plasticity- and axonal growth-associated protein GAP-43.; The first goal has been to study the role of transcriptional activity in regulating GAP-43 expression during development and in the adult, as well as activity-dependent signals possibly involved in it. By using transgenic mice bearing a lacZ gene under the control of the rat GAP-43 promoter (6 kb of the rat GAP-43 5{dollar}spprime{dollar} flanking sequence and 11 kb of the first intron), I have observed that during development of the hippocampal granule cells, the gene seems to act as a switch for axonal growth, following cell maturation, and preceding growth of their axons. The activation of the GAP-43 gene during development of the granule cell layer appears to be NMDA-independent, as assessed with chronic treatment with the NMDA receptor non-competitive antagonist MK-801. NMDA blockade does nonetheless reduce GAP-43 mRNA levels in granule cells, as well as mossy fiber growth. By studying transcriptional activity in olfactory system and lateral geniculate, it seems that GAP-43 gene regulation is cell-specific.; In the granule cell layer of the adult hippocampus, signals derived from hilar cell death seem to play a critical role in triggering GAP-43 expression and axonal growth, as observed after seizures in rodents, and humans, and Alzheimer's Disease patients, where hilar cell death occurs. Mossy fiber sprouting, normally not observed after seizures in mice, occurs in a strain of mice, 129SvEMs, that do show hilar cell death after epileptic activity, as opposed to those strains of mice where sprouting has not been found. In AD patients, hilar cell death is accompanied by increased GAP-43 immunoreactivity in the stratum lucidum of the hippocampus, indicative of mossy fiber sprouting. |
