The Role of the Septohippocampal Cholinergic System in Cognitive Functions

Cholinergic dysfunction is a hallmark of Alzheimer’s disease (AD). This dysfunction is assumed to be mainly responsible for the cognitive defects in AD. However, the mechanism by which the cholinergic system regulates cognitive functions is elusive. This study was designed to find out the role of the septohippocampal cholinergic system in cognitive functions. The methods used were behavioural testing (water maze, radial arm maze, passive avoidance and Y-maze) and electrophysiology (hippocampal EEG-recording and place cell recording). Apamin, a potassium channel blocker, was found to improve water maze spatial navigation of medial septal (MS) lesioned mice. The memory defect that is present in MS-lesioned mice was almost completely reversed by apamin. Apamin had no effect on the cognitive parameters of Y-maze and passive avoidance of MS-lesioned mice. The performance of intact mice was not affected. Apamin was also found to dose-dependently reverse the memory defect of hippocampal (HC) lesioned mice in radial arm maze. In the water maze, a similar observation was made: apamin improved the spatial navigation of HC-lesioned mice. Metrifonate, a cholinesterase inhibitor, was found to alleviate the memory defect of MS-lesioned mice. Metrifonate had no effect on the performance of intact mice. In contrast to apamin, metrifonate did not improve the water maze spatial navigation of hippocampal-lesioned mice. The effects of metrifonate and apamin were observed not to be mediated by modulation of the hippocampal theta rhythm in MS-lesioned mice. However, in intact mice, metrifonate induced changes in the hippocampal theta, and these changes were shown to be mediated by non-M1M2 muscarinic receptors. In addition, a selective cholinergic lesion of the septum was found to impair the ability of the hippocampus to remap in response to a new visual environment. In a familiar environment, the place fields of lesioned and sham operated animals had similar characteristics. However, upon subsequent exposures to the new environment, the place cell response in controls evolved in the direction of pattern separation, whereas in the lesioned animals the pattern evolved in the direction of pattern completion. As a result, the final representation of the new environment still resembled the familiar environment in the lesioned rats whereas a totally new representation developed in the controls. Taken together, the septohippocampal cholinergic system has at least two differential effects on the hippocampus: one, M1-mediated effect, regulates the cognitive functions, and the other, M3/M5-mediated effect, regulates hippocampal EEG. The effect on cognitive functions is likely to involve inhibition of afterhyperpolarisation. These findings support the role of the cholinergic system in the regulation of the predominant mode of the hippocampus: cholinergic innervation acts as a switch between the information gathering and information processing modes of the hippocampus. Thus, degeneration of the cholinergic system induces a memory defect by reducing the occurrence of information gathering mode. National Library of Medicine Classification: WL 314, WL 102, WT 155 Medical Subject Headings: Alzheimer disease; hippocampus; septum of brain; apamin; trichlorfon; cholinergic agents; receptors, muscarinic; spatial behavior; maze learning; memory; cognition; electroencephalography; theta rhythm; models, animal; mice; rats