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Hippocampal‐dependent memory is impaired in heterozygous GAP‐43 knockout mice

Cajal proposed that the rearrangement and growth of neurites and synaptic terminals is a substrate for the formation and storage of long‐term memories. Proteins that regulate this learning‐dependent growth are therefore likely to be “core determinants” (Sanes and Lichtman, Nat Neurosci 1999; 2:597–604) of such information storage processes. Although the growth‐associated, protein kinase C (PKC) substrate GAP‐43 has been oft‐implicated in synaptic plasticity and memory, it has never been demonstrated that a reduction in the level of this protein has a deleterious effect on memory, because most homozygotes die perinatally. In this report, we observe significant memory impairments in heterozygous GAP‐43 knockout mice with GAP‐43 levels reduced by one‐half. Impaired memory for a context was demonstrated in contextual fear conditioning. Importantly, no significant impairments in cued conditioning or on tests of nociceptive or auditory perception were observed in the heterozygous knockout, indicating that the observed impairments were unlikely related to performance or acquisition factors and are the result of reduced GAP‐43 levels in the hippocampus. The present results, taken together with the prior demonstration of enhanced memory in transgenic mice overexpressing GAP‐43, provide strong evidence for a pivotal role of hippocampal GAP‐43 in the bidirectional regulation of mnemonic processing. © 2004 Wiley‐Liss, Inc.