Alterations in Mossy fiber physiology and GAP-43 expression and function in transgenic mice overexpressing HuD

Daniel C. Tanner, Shenfeng Qiu, Federico Bolognani, L. Donald Partridge, Edwin J. Weeber, Nora I. Perrone-Bizzozero

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

HuD is a neuronal RNA-binding protein associated with the stabilization of mRNAs for GAP-43 and other neuronal proteins that are important for nervous system development and learning and memory mechanisms. To better understand the function of this protein, we generated transgenic mice expressing human HuD (HuD-Tg) in adult forebrain neurons. We have previously shown that expression of HuD in adult dentate granule cells results in an abnormal accumulation of GAP-43 mRNA via posttranscriptional mechanisms. Here we show that this mRNA accumulation leads to the ectopic expression of GAP-43 protein in mossy fibers. Electrophysiological analyses of the mossy fiber to CA3 synapse of HuD-Tg mice revealed increases in paired-pulse facilitation (PPF) at short interpulse intervals and no change in long-term potentiation (LTP). Presynaptic calcium transients at the same synapses exhibited faster time constants of decay, suggesting a decrease in the endogenous Ca2+ buffer capacity of mossy fiber terminals of HuD-Tg mice. Under resting conditions, GAP-43 binds very tightly to calmodulin sequestering it and then releasing it upon PKC-dependent phosphorylation. Therefore, subsequent studies examined the extent of GAP-43 phosphorylation and its association to calmodulin. We found that despite the increased GAP-43 expression in HuD-Tg mice, the levels of PKC-phosphorylated GAP-43 were decreased in these animals. Furthermore, in agreement with the increased proportion of nonphosphorylated GAP-43, HuD-Tg mice showed increased binding of calmodulin to this protein. These results suggest that a significant amount of calmodulin may be trapped in an inactive state, unable to bind free calcium, and activate downstream signaling pathways. In conclusion, we propose that an unregulated expression of HuD disrupts mossy fiber physiology in adult mice in part by altering the expression and phosphorylation of GAP-43 and the amount of free calmodulin available at the synaptic terminal.

Original languageEnglish (US)
Pages (from-to)814-823
Number of pages10
JournalHippocampus
Volume18
Issue number8
DOIs
StatePublished - 2008
Externally publishedYes

Keywords

  • GAP-43
  • HuD
  • Mossy fiber
  • Paired pulse facilitation
  • Residual calcium

ASJC Scopus subject areas

  • Cognitive Neuroscience

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