The effects of anti-nerve growth factor monoclonal antibodies on developing basal forebrain neurons are transient and reversible.
In order to reassess the role of nerve growth factor (NGF) on rat basal forebrain cholinergic neurons (BFCNs) survival and/or phenotype maturation during the early postnatal life, we immunoneutralized NGF in vivo. Hybridoma cells producing the neutralizing anti-NGF monoclonal antibody alphaD11 were implanted in the lateral ventricle of the rat at different postnatal ages (P2, P8 and P15) and the effects on the number and the soma size of cholinacetyltransferase (ChAT) positive neurons were analysed 1, 2 or 3 weeks after the injection. A marked decrease in the number and in the soma size of BFCNs was observed implanting hybridoma cells at P2 and performing the analysis 1 week later. These effects are reversed 3 weeks after the implant of hybridoma cells at P2. At this time point, the levels of alphaD11 antibodies in the brain parenchyma are still in a vast molar excess over endogenous NGF. No effects on BFCNs were observed implanting alphaD11 cells at P15 while LGN neurons showed marked shrinkage. Our results demonstrate that the reduction in the number of ChAT-positive neurons during the first two postnatal weeks of anti-NGF treatment is not due to cell death. We conclude that NGF is not a survival factor for BFCNs, and that the influence of NGF on BFCNs cell maturation during the first 2 postnatal weeks is transient and reversible. Our results on tyrosine kinase (Trk) coexpression, suggest that NGF may cooperate with other factors in the cholinergic phenotype differentiation and maintenance after the second postnatal week.
Molnar
M
M
SISSA International School of Advanced Studies, Neuroscience Program, Trieste, Italy.
Tongiorgi
E
E
Avignone
E
E
Gonfloni
S
S
Ruberti
F
F
Domenici
L
L
Cattaneo
A
A
D000367:Age Factors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000494:pharmacology*; D000918:Antibody Specificity; D001681:Biological Assay / Q000379:methods; D019556:COS Cells; D002452:Cell Count / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D017690:Cell Transplantation; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D002642:Chick Embryo; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis; D002799:Cholinergic Fibers / Q000187:drug effects; D002802:Cholinesterases / Q000032:analysis; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006825:Hybridomas; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D016716:PC12 Cells; D016548:Prosencephalon / Q000166:cytology* / Q000187:drug effects* / Q000254:growth & development; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D020801:Receptor, Ciliary Neurotrophic Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis; D013997:Time Factors
D000911:Antibodies, Monoclonal; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D002802:Cholinesterases