Presynaptic Inhibitory Effects of Acetylcholine in the Hippocampus: A 40-Year Evolution of a Serendipitous Finding

Abstract

Cholinergic regulation of hippocampal circuit activity has been an active area of neurophysiological research for decades. The prominent cholinergic innervation of intrinsic hippocampal circuitry, potent effects of cholinomimetic drugs, and behavioral responses to cholinergic modulation of hippocampal circuitry have driven investigators to discover diverse cellular actions of acetylcholine in distinct sites within hippocampal circuitry. Further research has illuminated how these actions organize circuit activity to optimize encoding of new information, promote consolidation, and coordinate this with recall of prior memories. The development of the hippocampal slice preparation was a major advance that accelerated knowledge of how hippocampal circuits functioned and how acetylcholine modulated these circuits. Using this preparation in the early 1980s, we made a serendipitous finding of a novel presynaptic inhibitory effect of acetylcholine on Schaffer collaterals, the projections from CA3 pyramidal neurons to dendrites of CA1 pyramidal cells. We characterized this effect at cellular and pharmacological levels, published the findings in the first volume of the Journal of Neuroscience, and proceeded to pursue other scientific directions. We were surprised and thrilled to see that, nearly 40 years later, the paper is still being cited and downloaded because the data became an integral piece of the foundation of the science of cholinergic regulation of hippocampal function in learning and memory. This Progressions article is a story of how single laboratory findings evolve through time to be confirmed, challenged, and reinterpreted by other laboratories to eventually become part of the basis of fundamental concepts related to important brain functions.

Cholinergic and Neuroimmune Signaling Interact to Impact Adult Hippocampal Neurogenesis and Alcohol Pathology Across Development

“…Despite evidence suggesting that there is no impact of ethanol on binding affinity or number of muscarinic receptor subtype, models of chronic ethanol exposure in adulthood do impair acetylcholine-mediated evoked electrophysiological post-synaptic potential responses in pyramidal cells of the CA1 region of the hippocampus, suggesting impaired cholinergic function in this region ( Rothberg and Hunter, 1991 ). Cholinergic activation of pyramidal cells is thought to be mediated through muscarinic receptors, as these effects can be blocked by the muscarinic atropine but not nicotinic agonists ( Cole and Nicoll, 1984 ; Valentino and Dingledine, 2021 ). This reduced hippocampal cellular responsivity to acetylcholine is postulated to be due to impaired intracellular transduction mechanisms following cholinergic muscarinic receptor activation, suggesting that chronic ethanol may alter muscarinic receptor function in the absence of overarching loss of receptor number.…”