Middle Cerebral Artery Occlusion Increases the Sensitivity of Cortical Neurons to Acetylcholine and Impairs Cognitive Function in Rats

The goal of the present study was to relate the degree of cortical cholinergic deafferentation induced by middle cerebral artery (MCA) occlusion to changes in the sensitivity of frontal cortical neurons to iontophoretic administration of acetylcholine (ACh) and to changes in cognitive performance in the Morris water maze in rats. In Wistar rats, MCA occlusion reduced the density of acetylcholinesterase (AChE)-positive fibers in the frontal cortex by 57% (n = 8) and the activity of cholineacetyltransferase (ChAT) by 59% (n = 5). The MCA occluded rats took significantly longer to locate the submerged platform in the water maze than sham-operated rats, although swim speeds were similar, at a time when neurological deficits were minimal. Basal neuronal firing rates were reduced after MCA occlusion. The percentage of neurons responding to ACh was increased but responses to carbachol and glutamate were unaffected. The increased sensitivity of cortical neurons to ACh correlated positively with the loss of AChE activity and with the impaired performance of the MCA-occluded rats in the water maze. The increased size of the responses to the cholinomimetics is probably due to increased sensitivity of post-synaptic cholinoceptors. These data confirm that MCA occlusion in the rat causes a loss of cortical AChE-positive fibers and behavioral effects which are suggestive of memory disruption. The increased proportion of neurons responding to ACh is likely to result from the loss of AChE activity. Loss of cholinergic neurons may contribute to the cognitive impairment seen in patients with cerebrovascular accidents or stroke.