title: Endogenous ciliary neurotrophic factor protects GABAergic, but not cholinergic, septohippocampal neurons following fimbria-fornix transection.
abstract: Application of neurotrophic proteins including ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), members of the family of gp130-associated cytokines, can rescue CNS neurons from injury-induced degeneration. However, it is not clear so far if these effects reflect a physiological function of the endogenous cytokines. Using fimbria-fornix transection as a model, we examined whether responses of GABAergic and cholinergic septohippocampal neurons to axotomy are altered in mice lacking CNTF. In addition, we studied the cellular expression of CNTF, LIF and related cytokine receptor components in the septal complex following lesion. Degeneration of septohippocampal GABAergic neurons in the medial septum as indicated by the loss of parvalbumin-immunoreactive neurons was accelerated and permanently enhanced in CNTF(-/-) mice as compared to wild-type animals. Unexpectedly, the number of axotomized cholinergic MS neurons was significantly higher in CNTF-deficient mice during the first 2 weeks postlesion. Both in wild-type and in CNTF(-/-) mutants, expression of mRNA for the CNTF-specific alpha-subunit of the cytokine receptor complex was specifically upregulated in axotomized GABAergic septal neurons, whereas enhanced expression of the LIF-binding beta-subunit was specifically observed in axotomized cholinergic neurons. Following lesion, CNTF expression in wild-type mice was induced in activated astrocytes surrounding the axotomized neurons and at the lesion site. Expression of LIF mRNA was localized in the GABAergic and cholinergic septohippocampal neurons. These results strongly indicate that endogenous CNTF, supplied by reactive glia cells, acts as a neuroprotective factor for axotomized CNS neurons. In the septum, endogenous CNTF specifically supports lesioned GABAergic projection neurons, whereas LIF may play a similar role for the cholinergic counterparts.
authors.affiliation: Institute of Anatomy, University of Freiburg, Germany. Thomas.Naumann@anat.uni-freiburg.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Naumann
authors.forename: Oliver
authors.initials: O
authors.lastname: Schnell
authors.forename: Qixia
authors.initials: Q
authors.lastname: Zhi
authors.forename: Matthias
authors.initials: M
authors.lastname: Kirsch
authors.forename: Klaus Oliver
authors.initials: KO
authors.lastname: Schubert
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Hofmann
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D019771:Axotomy; D016022:Case-Control Studies; D002452:Cell Count; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D020712:Fornix, Brain / Q000378:metabolism* / Q000473:pathology; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism*; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020801:Receptor, Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012686:Septal Nuclei / Q000166:cytology / Q000378:metabolism*; D013266:Stilbamidines; D016019:Survival Analysis; D013997:Time Factors
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D020934:Ciliary Neurotrophic Factor; D018076:DNA, Complementary; D005456:Fluorescent Dyes; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D010320:Parvalbumins; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D013266:Stilbamidines; D000110:Acetylcholinesterase