Advanced

Effects of neonatal lesions of the basal forebrain cholinergic system by 192 immunoglobulin G-saporin : biochemical, behavioural and morphological characterization

Leanza, G LU ; Nilsson, O G LU ; Nikkhah, G ; Wiley, R G and Björklund, A LU (1996) In Neuroscience 74(1). p.41-119
Abstract

Selective removal of the basal forebrain cholinergic neurons by the immunotoxin 192 immunoglobulin G-saporin has offered a new powerful tool for the study of the relationships between cholinergic dysfunction and cognitive impairments. In the present study the morphological and functional consequences of selective lesions of the basal forebrain cholinergic system during early postnatal development have been investigated following bilateral intraventricular injections of 192 immunoglobulin G-saporin to immature (four-day-old) rats. Administration of increasing doses (0.2-0.8 microgram) of the immunotoxin produced dose-dependent loss of cholinergic neurons in the septal/diagonal band area (up to 72-86%) and in the nucleus basalis... (More)

Selective removal of the basal forebrain cholinergic neurons by the immunotoxin 192 immunoglobulin G-saporin has offered a new powerful tool for the study of the relationships between cholinergic dysfunction and cognitive impairments. In the present study the morphological and functional consequences of selective lesions of the basal forebrain cholinergic system during early postnatal development have been investigated following bilateral intraventricular injections of 192 immunoglobulin G-saporin to immature (four-day-old) rats. Administration of increasing doses (0.2-0.8 microgram) of the immunotoxin produced dose-dependent loss of cholinergic neurons in the septal/diagonal band area (up to 72-86%) and in the nucleus basalis magnocellularis (up to 91-93%), paralleled by marked reductions in choline acetyltransferase activity in the hippocampus and several cortical regions (73-84%). The parvalbumin-positive neurons in the septal/diagonal band area and the calbindin-positive Purkinje cells in the cerebellum were unaffected at all dose levels. Brain dopamine or noradrenaline levels were unaffected or increased by the immunotoxin treatment. At the optimal dose, 0.4 microgram, the toxin conjugate produced maximal cholinergic depletion without significant mortality. Higher doses (0.8, 1.2 and 1.6 micrograms) of toxin, on the other hand, proved to be lethal for most or all of the injected animals. When tested at three and eight months after the optimal dose, in spite of persisting cholinergic depletion, the noenatally lesioned animals showed no impairment in the water maze task or in locomotor activity and exploration as compared to normal controls, probably reflecting partial sparing of the cholinergic neurons by the neonatal immunotoxic lesion (above all in the vertical and horizontal limbs of the diagonal band area), and/or a greater degree of plasticity in the developing as compared to the mature cholinergic system. The place navigational performance of the neonatally lesioned animals in the water maze task was abolished by central muscarinic cholinergic receptor blockade (by atropine) or by a second immunotoxic lesion, which eliminated virtually all residual cholinergic neurons in the septal/diagonal band area and the nucleus basalis. Administration of 192 immunoglobulin G-saporin to similarly trained, but previously normal adult rats, produced similar cholinergic depletions but much less severe place navigation deficits, suggesting that preoperative training on the task may reduce the functional consequences of a subsequent cholinergic lesion. The results thus support the view that the basal forebrain cholinergic system may be implicated in the acquisition rather than retention of spatial memory in the water maze task.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Animals, Newborn/metabolism, Antineoplastic Agents, Phytogenic/pharmacology, Cholinergic Fibers/drug effects, Dose-Response Relationship, Drug, Female, Immunotoxins, Male, N-Glycosyl Hydrolases, Plant Proteins/pharmacology, Prosencephalon/drug effects, Rats, Rats, Sprague-Dawley, Ribosome Inactivating Proteins, Type 1, Saporins
in
Neuroscience
volume
74
issue
1
pages
23 pages
publisher
Elsevier
external identifiers
  • pmid:8843082
  • scopus:0029762386
ISSN
0306-4522
DOI
10.1016/0306-4522(96)00095-4
language
English
LU publication?
yes
id
0d03d3f7-469a-4b14-8ed6-b2b09e0f8b04
date added to LUP
2019-06-25 09:51:27
date last changed
2020-01-13 02:06:14
@article{0d03d3f7-469a-4b14-8ed6-b2b09e0f8b04,
  abstract     = {<p>Selective removal of the basal forebrain cholinergic neurons by the immunotoxin 192 immunoglobulin G-saporin has offered a new powerful tool for the study of the relationships between cholinergic dysfunction and cognitive impairments. In the present study the morphological and functional consequences of selective lesions of the basal forebrain cholinergic system during early postnatal development have been investigated following bilateral intraventricular injections of 192 immunoglobulin G-saporin to immature (four-day-old) rats. Administration of increasing doses (0.2-0.8 microgram) of the immunotoxin produced dose-dependent loss of cholinergic neurons in the septal/diagonal band area (up to 72-86%) and in the nucleus basalis magnocellularis (up to 91-93%), paralleled by marked reductions in choline acetyltransferase activity in the hippocampus and several cortical regions (73-84%). The parvalbumin-positive neurons in the septal/diagonal band area and the calbindin-positive Purkinje cells in the cerebellum were unaffected at all dose levels. Brain dopamine or noradrenaline levels were unaffected or increased by the immunotoxin treatment. At the optimal dose, 0.4 microgram, the toxin conjugate produced maximal cholinergic depletion without significant mortality. Higher doses (0.8, 1.2 and 1.6 micrograms) of toxin, on the other hand, proved to be lethal for most or all of the injected animals. When tested at three and eight months after the optimal dose, in spite of persisting cholinergic depletion, the noenatally lesioned animals showed no impairment in the water maze task or in locomotor activity and exploration as compared to normal controls, probably reflecting partial sparing of the cholinergic neurons by the neonatal immunotoxic lesion (above all in the vertical and horizontal limbs of the diagonal band area), and/or a greater degree of plasticity in the developing as compared to the mature cholinergic system. The place navigational performance of the neonatally lesioned animals in the water maze task was abolished by central muscarinic cholinergic receptor blockade (by atropine) or by a second immunotoxic lesion, which eliminated virtually all residual cholinergic neurons in the septal/diagonal band area and the nucleus basalis. Administration of 192 immunoglobulin G-saporin to similarly trained, but previously normal adult rats, produced similar cholinergic depletions but much less severe place navigation deficits, suggesting that preoperative training on the task may reduce the functional consequences of a subsequent cholinergic lesion. The results thus support the view that the basal forebrain cholinergic system may be implicated in the acquisition rather than retention of spatial memory in the water maze task.</p>},
  author       = {Leanza, G and Nilsson, O G and Nikkhah, G and Wiley, R G and Björklund, A},
  issn         = {0306-4522},
  language     = {eng},
  number       = {1},
  pages        = {41--119},
  publisher    = {Elsevier},
  series       = {Neuroscience},
  title        = {Effects of neonatal lesions of the basal forebrain cholinergic system by 192 immunoglobulin G-saporin : biochemical, behavioural and morphological characterization},
  url          = {http://dx.doi.org/10.1016/0306-4522(96)00095-4},
  doi          = {10.1016/0306-4522(96)00095-4},
  volume       = {74},
  year         = {1996},
}