Up-regulation of growth-associated protein 43 mRNA in rat medial septum neurons axotomized by fimbria-fornix transection.

Abstract

Transection of septohippocampal fibres is widely used to study the response of CNS neurons to axotomy. Septohippocampal projection neurons survive axotomy and selectively up-regulate the transcription factor c-Jun. In the present study we investigated whether these cells concomitantly up-regulate the growth-associated protein-43 (GAP-43), a potential target gene of c-Jun implicated in axonal growth and regeneration. Using in situ hybridization histochemistry (ISHH) it was demonstrated that postlesional c-jun mRNA expression is accompanied by an increased expression of GAP-43 mRNA in the medial septum 3 days following fimbria-fornix transection (FFT). The increase reached a maximum at 7 days and gradually declined thereafter (17 days, 3 weeks). Retrograde prelabeling with Fluoro-Gold followed by axotomy and ISHH revealed that GAP-43 mRNA was up-regulated in septohippocampal projection neurons. Colocalization of GAP-43 mRNA and choline acetyltransferase protein showed that GAP-43 mRNA was expressed by cholinergic medial septal neurons after axotomy. Selective immunolesioning of the cholinergic component of the septohippocampal projection with 192 IgG-saporin followed by FFT demonstrated that GAP-43 mRNA was also synthesized by axotomized GABAergic neurons. These results demonstrate an up-regulation of GAP-43 mRNA in axotomized septohippocampal projection neurons independent of their transmitter phenotype which is closely correlated with c-Jun expression. Because the GAP-43 gene contains an AP-1 site, we hypothesize a c-Jun-driven up-regulation of GAP-43 in lesioned medial septal neurons that may contribute to their survival and regenerative potential following axotomy.