NEUROTROPHIN-4 5 MAINTAINS THE CHOLINERGIC PHENOTYPE OF AXOTOMIZED SEPTAL NEURONS/

We examined the effect of intraseptal or intracerebroventricular (i.c. v.) infusions of NT-4/5 or intraseptal infusions of NGF on the level o f immunohistochemical staining of choline acetyltransferase (ChAT) and the low-affinity nerve growth factor receptor (LNGFR) in the rat medi al septum following unilateral transection of the fimbria. The extent of cell loss in the septum ipsilateral to the lesion, determined by ce ll counts of ChAT-immunopositive neurons and expressed as a ratio comp aring the lesioned to the intact sides, was 0.28 in animals that recei ved an infusion of phosphate-buffered saline (PBS). The ratios were 0. 97 and 1.07 in animals that received an infusion of NT-4/5 into the ip silateral ventricle and septum respectively. Septal infusions of NGF p roduced a ratio of ChAT-immunopositive cells of 1.03. The ratios of LN GFR-immunopositive neurons increased from 0.50 in PBS-infused animals to 0.79 and 0.83 in animals infused with NT-4/5 via the i.c.v. and sep tal routes respectively, and to 0.89 with NGF via the septal route. Tr ansection of the fimbria also reduced the expression of TrkA in the ip silateral medial septum and vertical limb of the diagonal band of Broc a in PBS-infused animals. The loss of TrkA was ameliorated by either i .c.v. infusion of NT-4/5 or septal infusion of NT-4/5 or NGF. As deter mined by immunohistochemical staining, NT-4/5 infused into the lateral ventricle was detected in the periventricular portions of the forebra in ipsilateral to the infusion, while NT-415 or NGF infused intrasepta lly was detected in much of the septum, bilaterally. Furthermore, exog enous NT-415 or NGF was detected in numerous neuronal perikarya in the medial septal and diagonal band nuclei. These data demonstrate that, as with NGF, i.c.v. as well as septal infusions of NT-4/5 can maintain the phenotype of basal forebrain cholinergic neurons following axotom y.