The Journal of Neuroscience, October 15, 2001, 21(20):8164-8173
Selective Immunolesions of Cholinergic Neurons in Mice: Effects
on Neuroanatomy, Neurochemistry, and Behavior
Joanne
Berger-Sweeney1,
Nancy A.
Stearns1,
Stephanie L.
Murg2,
Laura
R.
Floerke-Nashner1,
Douglas A.
Lappi3, and
Mark G.
Baxter2
1 Department of Biological Sciences, Wellesley College,
Wellesley, Massachusetts 02481, 2 Department of Psychology,
Harvard University, Cambridge, Massachusetts 02138, and
3 Advanced Targeting Systems, San Diego, California 92121
The ability to selectively lesion mouse basal forebrain cholinergic
neurons would permit experimental examination of interactions between
cholinergic functional loss and genetic factors associated with
neurodegenerative disease. We developed a selective toxin for mouse
basal forebrain cholinergic neurons by conjugating saporin (SAP), a
ribosome-inactivating protein, to a rat monoclonal antibody against the
mouse p75 nerve growth factor (NGF) receptor (anti-murine-p75). The toxin proved effective and selective in vitro and
in vivo. Intracerebroventricular injections of
anti-murine-p75-SAP produced a dose-dependent loss of choline
acetyltransferase (ChAT) activity in the hippocampus and neocortex
without affecting glutamic acid decarboxylase (GAD) activity.
Hippocampal ChAT depletions induced by the immunotoxin were
consistently greater than neocortical depletions. Immunohistochemical
analysis revealed a dose-dependent loss of cholinergic neurons in the
medial septum (MS) but no marked loss of cholinergic neurons in the
nucleus basalis magnocellularis after
intracerebroventricular injection of the toxin. No loss of
noncholinergic neurons in the MS was apparent, nor could we detect loss
of noncholinergic cerebellar Purkinje cells, which also express p75.
Behavioral analysis suggested a spatial learning deficit in
anti-murine-p75-SAP-lesioned mice, based on a correlation between a
loss of hippocampal ChAT activity and impairment in Morris water maze
performance. Our results indicate that we have developed a specific
cholinergic immunotoxin for mice. They also suggest possible functional
differences in the mouse and rat cholinergic systems, which may be of
particular significance in attempts to develop animal models of human
diseases, such as Alzheimer's disease, which are associated with
impaired cholinergic function.
Key words:
Alzheimer's disease; basal forebrain; cholinergic; immunotoxin; saporin; p75
Copyright © 2001 Society for Neuroscience 0270-6474/01/21208164-10$05.00/0
Previous Article | Next Article
