GAP-43 gene expression regulates information storage

Abstract

Previous reports have shown that overexpression of the growth-and plasticity-associated protein GAP-43 improves memory. However, the relation between the levels of this protein to memory enhancement remains unknown. Here, we studied this issue in transgenic mice (G-Phos) overexpressing native, chick GAP-43. These G-Phos mice could be divided at the behavioral level into "spatial bright" and "spatial dull" groups based on their performance on two hidden platform water maze tasks. G-Phos dull mice showed both acquisition and retention deficits on the fixed hidden platform task, but were able to learn a visible platform task. G-Phos bright mice showed memory enhancement relative to wild type on the more difficult movable hidden platform spatial memory task. In the hippocampus, the G-Phos dull group showed a 50% greater transgenic GAP-43 protein level and a twofold elevated transgenic GAP-43 mRNA level than that measured in the G-Phos bright group. Unexpectedly, the dull group also showed an 80% reduction in hippocampal Tau1 staining. The high levels of GAP-43 seen here leading to memory impairment find its histochemical and behavioral parallel in the observation of Rekart et al. (Neuroscience 126 126: 579-584) who described elevated levels of GAP-43 protein in the hippocampus of Alzheimer's patients. The present data suggest that moderate overexpression of a phosphorylatable plasticity-related protein can enhance memory, while excessive overexpression may produce a "neuroplasticity burden" leading to degenerative and hypertrophic events culminating in memory dysfunction.The growth-and plasticity-associated protein, GAP-43, plays a central role in the learning and memory process. GAP-43 is neuron-specific (Chan et al. 1986;Basi et al. 1987;Alexander et al. 1988;Liu and Storm 1989;Skene and Virag 1989;Zuber et al. 1989;Nielander et al. 1990), is found in high concentrations in growth cones (Nelson et al. 1989), and is closely associated with regenerative and developmental growth (Skene 1989;Strittmatter et al. 1995). Its activity is regulated by a protein kinase C (PKC) phosphorylation site (Alexander et al. 1988;De Graan et al. 1990a) embedded within a calmodulin-binding domain (Alexander et al. 1988) that exist in a yin-yang relation. GAP-43 demonstrates a direct relation between its phosphorylation state and enhancement of LTP (Lovinger et al. 1985(Lovinger et al. , 1986Lovinger and Routtenberg 1988;Gianotti et al. 1992) as well as behavioral learning (Routtenberg and Ehrlich 1975;Ehrlich et al. 1977;Cammarota et al. 1997;Young et al. 2000Young et al. , 2002, suggesting a pivotal role for this presynaptic protein in mnemonic function (for reviews, see Routtenberg 1987, 1997;Perrone Bizzozero and Tanner 2006).Transgenic overexpression of the phosphorylatable (GPhos), but not the nonphosphorylatable (G-NonP) or permanently (pseudo)phosphorylated (G-Perm), form of GAP-43 in mice enhanced memory on a radial arm maze task (Routtenberg et al. 2000). This selective enhancement demonstrated that the PKC phosphorylation s...

Alterations in mossy fiber physiology and GAP‐43 expression and function in transgenic mice overexpressing HuD

“…The changes in behavior of our HuD OE mice appeared to be different from GAP-43 OE mice, which show increased learning of a delayed non-matching to sample task . Interestingly, a recent study suggests that not all of the GAP-43 OE mice have increased learning abilities and animals that have excessive amounts of GAP-43 in the hippocampus show substantial learning and memory deficits (Holahan et al, 2007). It will therefore be of interest to determine whether the levels of GAP-43 considered excessive in that report are close to those generated in the present study.…”

Catalpol Upregulates Hippocampal GAP-43 Level of Aged Rats with Enhanced Spatial Memory and Behavior Response

“…Correlation analysis showed that the increased hippocampal levels of GAP-43 induced by catalpol treatment was associated with spatial memory performance, those rats with higher hippocampal GAP-43 expression required less trial times to reach learning criterion, and they showed more correct response to avoid foot shocks in the retention experiment. Studies by others have suggested the amount of GAP-43 in the hippocampus is significantly correlated with performance in the memory task [3,28], and they are consistent with our findings. We can draw a conclusion that catalpol may increase memory by up-regulating GAP-43 level in the hippocampus of aged dementia rats.…”

The protein kinase C phosphorylation site on GAP‐43 differentially regulates information storage

“…In the third task used, the Morris water maze (for methods, see Holahan et al, 2007), differential performance among the 3 transgenic lines was also revealed. Here the G-NonP mice (n = 6) distinguished themselves by their poor retention performance on the probe test relative to the other groups (Fig 1C and D).…”