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

Rekart, Jerome L.; Meiri, Karina F.; Routtenberg, Aryeh

doi:10.1002/hipo.20045

Cited by 89 publications

(59 citation statements)

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“…Moreover, others have shown that elevations of GAP-43 protein immunolabeling in the anterior cingulate have been linked to remote memory formation (Maviel et al 2004), and training on a water maze task elevates GAP-43 protein and mRNA expression in the hippocampus compared with swim controls (Pascale et al 2004). GAP-43 heterozygote knockout mice with a 50% reduction in endogenous GAP-43 show impaired retention for a contextual fear-conditioning task (Rekart et al 2005). These data indicate that GAP-43 protein levels prior to behavioral testing can finely calibrate behavioral memory performance, while such performance can then, in turn, In a previous report, both wild-type and G-Phos mice acquired the standard radial arm maze at similar rates.…”

Section: Discussionmentioning

confidence: 99%

GAP-43 gene expression regulates information storage

Holahan¹,

Honegger²,

Tabatadze³

et al. 2007

Learn. Mem.

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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...

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Section: Discussionmentioning

confidence: 99%

GAP-43 gene expression regulates information storage

Holahan¹,

Honegger²,

Tabatadze³

et al. 2007

Learn. Mem.

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“…In addition the neuronal proliferation is also affected (Mani et al 2001;Shen et al 2008). Reflecting these structural defects GAP-43 knockout mice also show functional defects including memory impairment and sensorimotor disorder (Metz and Schwab 2004;Rekart et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of GAP-43 Protein in the Rostral Brain Neurons of Early Chick Embryos

Onodera

Kakehata

Araki

2013

Tohoku J. Exp. Med.

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Brain development is composed of several processes, which are chronologically and mechanistically overlapping each other. However, the process of the earliest neural circuit formation in the rostral brain is less understood compared with other processes in brain development, in part because of the lack of appropriate molecular markers. Accordingly, the identification of molecular markers for nerve cells may accelerate the detailed analysis of neural development. Growth associated protein 43 (GAP-43) is a major growth cone protein that regulates F-actin dynamics, and it has been often used as a marker for developing neurons. To test whether GAP-43 can be used as a general marker for developing neurons in chick early embryos, we analyzed the expression pattern of GAP-43 protein in the brain. While the majority of the neurons were GAP-43 positive, the earliest neurons in the dorsal mesencephalon (future tectum) were GAP-43 negative. However, a subset of the GAP-43 negative neurons became positive at later stages. Such a difference in the expression of GAP-43 protein may contribute to the precise patterning of the neural circuits in the mesencephalon in the subsequent development. The earliest neurons in the telencephalon, which belong to the terminal nerve (TN), were also GAP-43 positive. Since the development of TN is poorly understood compared to other cranial nerves, GAP-43 could help the detailed analysis of the development of TN as the marker.Keywords: chick embryo; descending tract of the mesencephalic nucleus of the trigeminus; growth associated protein 43; pioneer neuron; terminal nerve Tohoku J. Exp. Med., 2013 December, 231 (4), 293-298.

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“…In the second task employed, contextual fear conditioning (see Rekart et al, 2005, for methods), the G-Perm group (n = 7), in striking contrast to the other groups, showed the highest levels of freezing on Day 21 as well as the best retention scores indicated by the persistently high levels of freezing over the course of subsequent testing (Fig 1B). In contrast, the G-Phos group (n = 9), showed an accelerated rate of extinction differing from the other groups.…”

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

Holahan

Routtenberg

2008

Hippocampus

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Protein kinase C (PKC) is known to regulate phosphorylation of substrates such as MARCKS, GAP-43 and the NMDA receptor, all of which have been linked to synaptic plasticity underlying information storage processes. Here we report on 3 transgenic mice isoforms differentiated both by mutation of the PKC site on GAP-43 as well as by their performance in 3 learning situations: 1) a radial arm maze task, which evaluates spatial memory and its retention, 2) fear conditioning which assesses contextual memory and 3) the water maze which also evaluates spatial memory and its retention. The present results show, for the first time to our knowledge, that the phosphorylation state of a single site on an identified brain growth-and plasticity-associated protein differentially regulates performance of 3 different memory-associated tasks.Post-translational modification of synaptic proteins already synthesized and located at preand post-synaptic sites has been proposed as a critical event leading to long-lasting information storage (Routtenberg, 1985;Routtenberg and Rekart, 2005;Routtenberg, 2008).

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

Cited by 89 publications

References 46 publications

GAP-43 gene expression regulates information storage

GAP-43 gene expression regulates information storage

Differential Expression of GAP-43 Protein in the Rostral Brain Neurons of Early Chick Embryos

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

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