Enhanced learning after genetic overexpression of a brain growth protein

Ramon y Cajal proposed 100 years ago that memory formation requires the gro wth of nerve cell processes. One-half century later, Hebb suggested that gr owth of presynaptic axons and postsynaptic dendrites consequent to coactivi ty in these synaptic elements was essential for such information storage. I n the past 25 years, candidate growth genes have been implicated in learnin g processes, but it has not been demonstrated that they in fact enhance the m. Here, we show that genetic overexpression of the growth-associated prote in GAP-43, the axonal protein kinase C substrate, dramatically enhanced lea rning and long-term potentiation in transgenic mice. If the overexpressed G AP-43 was mutated by a Ser --> Ala substitution to preclude its phosphoryla tion by protein kinase C, then no learning enhancement was found. These fin dings provide evidence that a growth-related gene regulates learning and me mory and suggest an unheralded target, the GAP-43 phosphorylation site, for enhancing cognitive ability.