Alzheimer's disease is the most common form of dementia in North America today. Though many risk factors have been suggested to increase the likelihood of developing this disease, an accurate etiology has yet to be described. One of these risk factors commonly associated with Alzheimer's disease is the loss of cholinergic neurons of the medial septum that project to the hippocampus, leading to depletion in cholinergic activity. A second risk factor is the presence of seizures, which can increase the risk of excitotoxic cell death. To examine the interaction between these two common risk factors, we gave rats a focal cholinergic lesion of the medial septum using the specific immunotoxin 192-IgG Saporin, followed 2 weeks later by a non-convulsive dose of kainic acid. We then assessed the rats for seizure severity, hippocampal damage and performance on a spatial memory task. The combination of the two factors resulted in a trend towards increased seizure severity in the cholinergic depleted rats, but more importantly, the lesioned rats that had non-convulsive seizures were significantly impaired on a spatial version of the Morris water maze when compared with either the rats with a cholinergic depletion or non-convulsive seizure alone. This result could not be explained by seizure severity or the extent of hippocampal damage, suggesting a more subtle interaction between these two risk factors in the development of a hippocampal based memory impairment.
A consistent finding in patients suffering from Alzheimer's disease is a loss of the cholinergic neurons of the basal forebrain that project to the hippocampus. However, the role this depletion plays in the development of Alzheimer's disease remains unclear. The loss of this ascending neurotransmitter system could potentially render hippocampal neurons more susceptible to further insult, such as chronic stress, ultimately resulting in neuronal death and memory loss. We explored this possibility by using the highly specific toxin 192 IgG-Saporin to destroy the majority of cholinergic activity in the septo-hippocampal pathway in rats. Following depletion, rats were subjected to 2 weeks of restraint stress. Rats were divided into two groups and were tested either on a hippocampal-dependent (water maze) task or a hippocampal-independent task (fear conditioning to tone and context). We showed that cholinergic depletion or stress alone had no effect on the successful performance of either of the tasks. However, rats with a combination of cholinergic depletion and stress were significantly impaired on the water-maze task. No deficits were apparent in the combined group that was tested on fear conditioning to tone or context, suggesting that this impairment is specific to spatial working memory. These rats had no obvious hippocampal neuronal loss or damage; however, there were likely subtle changes in hippocampal processing that led to the observed deficit on the hippocampal-dependent task. These findings support our theory that cholinergic depletion of the medial septum increases hippocampal vulnerability to further insults such as stress.
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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