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Selective lesion of medial septal cholinergic neurons followed by a mini-stroke impairs spatial learning in rats

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Abstract

Reduced levels of hippocampal acetylcholine are a common finding in patients diagnosed with Alzheimer’s disease, but it remains unclear what role this depletion plays in the development of dementia. It is possible that the reduced levels of acetylcholine increases the vulnerability of hippocampal neurons to future insults which could lead to neuronal death and cognitive impairment. One insult that is commonly observed in the demented elderly and often co-exists with Alzheimer’s disease is stroke. In the current experiment, we used the immunotoxin 192 IgG-Saporin to specifically lesion the cholinergic neurons of the medial septum that project to the hippocampus. We then explored the effects of small, localised strokes in the hippocampus on spatial learning and memory. The combination of cholinergic depletion and stroke resulted in significant impairment on the spatial water maze compared to the performance of rats receiving either factor alone. Quantification of hippocampal damage revealed no difference in the overall lesion size of stroke-only or combined (cholinergic depletion and stroke) rats, suggesting that a more subtle mechanism is responsible for the observed impairment. We propose that healthy hippocampal neurons may normally be able to withstand, and compensate for a small ischemic insult. However, in the absence of cholinergic projections from the medial septum, these compensatory processes in the hippocampus may be compromised resulting in the spatial learning impairment reported here. This suggests an association between the cholinergic depletion observed during aging and the potential for functional recovery following stroke.

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Abbreviations

ACh:

Acetylcholine

AChE:

Acetylcholinesterase

AD:

Alzheimer’s disease

ANOVA:

Analysis of variance

BDNF:

Brain-derived neurotrophic factor

ChAT:

Choline acetyltransferase

DAB:

Diaminobenzidine

GABA:

γ-Aminobutyric acid

IgG-SAP:

192 IgG-Saporin

MS/VDM:

Medial septum and vertical limb of the diagonal band of Broca

NGF:

Nerve growth factor

PBS:

Phosphate buffered saline

PFA:

Paraformaldehyde

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Acknowledgments

Dr. Robert McDonald is currently a Canada Research Chair. This research was supported by grants awarded to RJM from the Canadian Stroke Network, and Natural Sciences and Engineering Research Council agencies; and to LAC from the Alzheimer’s Society of Canada.

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Authors and Affiliations

  1. Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB, T1K 3M4, Canada

    Laura A. Craig, Nancy S. Hong, Joelle Kopp & Robert J. McDonald

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  1. Laura A. Craig
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  2. Nancy S. Hong
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  3. Joelle Kopp
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  4. Robert J. McDonald
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Correspondence to Laura A. Craig.

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Craig, L.A., Hong, N.S., Kopp, J. et al. Selective lesion of medial septal cholinergic neurons followed by a mini-stroke impairs spatial learning in rats. Exp Brain Res 193, 29–42 (2009). https://doi.org/10.1007/s00221-008-1592-5

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  • DOI: https://doi.org/10.1007/s00221-008-1592-5

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