Loss of developing cholinergic basal forebrain neurons following excitotoxic lesions of the hippocampus: rescue by neurotrophins.
Previous studies have demonstrated that the viability of developing cholinergic basal forebrain neurons is dependent upon the integrity of neurotrophin-secreting target cells. In the present study, we examined whether infusions of nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) could prevent the loss of cholinergic septal/diagonal band neurons following excitotoxic lesions of their target neurons within the hippocampus. Postnatal Day 10 rat pups received unilateral intrahippocampal injections of ibotenic acid. Rats then received intracerebroventricular (icv) injections of nerve growth factor (30 micrograms/injection), brain-derived neurotrophic factor (60 micrograms/injection), or saline immediately following the lesion and continuing every third day for 27 days. Both saline- and BNDF-treated rats displayed a significant loss of septal/diagonal band neurons expressing the protein and mRNA for choline acetyltransferase (ChAT) and p75 low-affinity nerve growth factor receptor ipsilateral to the lesion. The magnitude of this loss was significantly attenuated in BNDF-treated rats. Many remaining neurons were atrophic with stunted dendritic processes. In contrast, NGF treatment completely rescued these cells and prevented the shrinkage of remaining cholinergic septal neurons. In addition, both NGF and BDNF induced a sprouting of cholinergic processes within the residual hippocampal remnant ipsilateral to the infusions. The present study demonstrates that icv injections of NGF, and to a lesser extent BDNF, prevent the loss of developing basal forebrain neurons which occurs following removal of normal target cells. Diffusion studies revealed relatively poor penetration of BDNF into brain parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)
Burke
M A
MA
Department of Anatomy and Cell Biology, University of Illinois School of Medicine, Chicago 60612.
Mobley
W C
WC
Cho
J
J
Wiegand
S J
SJ
Lindsay
R M
RM
Mufson
E J
EJ
Kordower
J H
JH
D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor; D002470:Cell Survival; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development*; D007051:Ibotenic Acid / Q000494:pharmacology; D017403:In Situ Hybridization; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000502:physiology; D010275:Parasympathetic Nervous System / Q000254:growth & development* / Q000473:pathology; D016548:Prosencephalon / Q000254:growth & development* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D012688:Septum Pellucidum / Q000166:cytology / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D007051:Ibotenic Acid; D002795:Choline O-Acetyltransferase