Ectopic growth of hippocampal mossy fibers in a mutated GAP-43 transgenic mouse with impaired spatial memory retention

In a previous study, it was shown that transgenic mice, designated G‐NonP, forget the location of a water maze hidden platform when tested 7 days after the last training day (Holahan and Routtenberg (2008) Hippocampus 18:1099–1102). The memory loss in G‐NonP mice might be related to altered hippocampal architecture suggested by the fact that in the rat, 7 days after water maze training, there is discernible mossy fiber (MF) growth (Holahan et al. (2006) Hippocampus 16:560–570; Rekart et al. (2007) Learn Mem 14:416–421). In the present report, we studied the distribution of the MF system within the hippocampus of naïve, untrained, G‐NonP mouse. In WT mice, the MF projection was restricted to the stratum lucidum of CA3 with no detectable MF innervation in distal stratum oriens (dSO). In G‐NonP mice, in contrast, there was an ectopic projection terminating in the CA3 dSO. Unexpectedly, there was nearly a complete loss of immunostaining for the axonal marker Tau1 in the G‐NonP transgenic mice in the MF terminal fields indicating that transgenesis itself leads to off‐target consequences (Routtenberg (1996) Trends Neurosci 19:471–472). Because transgenic mice overexpressing nonmutated, wild type GAP‐43 do not show this ectopic growth (Rekart et al., in press) and the G‐NonP mice overexpress a mutated form of GAP‐43 precluding its phosphorylation by protein kinase C (PKC), the possibility exists that permanently dephosphorylated GAP‐43 disrupts normal axonal fasciculation which gives rise to the ectopic growth into dSO. © 2009 Wiley‐Liss, Inc.