Acetylcholine and Memory

Even at the turn of the century, physicians knew that cholinergic drugs such as scopolamine, which blocks muscarinic acetylcholine receptors, could cause people to forget what happened while they were under the influence of the drug. A wide range of psychopharmacological studies in humans and animals have shown that scopolamine impairs the learning of new information. But this effect of cholinergic drugs has not been linked to specific effects of acetylcholine within cortical structures.

Physiological experiments using brain slice preparations of cortical structures have shown the specific effects of acetylcholine and cholinergic agonists (drugs which imitate acetylcholine) such as carbachol. Acetylcholine enhances the activity of many cortical neurons, causing suppression of membrane potassium currents and thereby causing depolarization and suppression of adaptation. This could certainly enhance memory function. However, many studies show that, along with suppressing adaptation of neurons, acetylcholine also suppresses synaptic transmission. If acetylcholine is important for new learning, why would it suppress synaptic transmission. This paradoxical combination of effects was clarified when it was found that the suppression of synaptic transmission is selective for intrinsic synapses (connections between cortical neurons), but not for afferent synapses (connections arising from outside the cortex). This effect was shown in the piriform cortex by Hasselmo and Bower (1992), and in hippocampal subregion CA1 by Hasselmo and Schnell (1994). Computational modeling of cortical function shows that this selective suppression of synaptic transmission can prevent recall of previously stored information from interfering with the learning of new information, as described in Hasselmo and Bower (1993) Trends Neurosci. 16: 218-222 and in Hasselmo (1993) Neural Comp. 5: 32-44. Later work showed how changes in synaptic currents during theta rhythm could separate phases of encoding and retrieval, preventing interference from previously formed representations (Hasselmo et al., 2002).

The figure here shows the selective suppression of synaptic transmission found in the piriform cortex. The schematic diagram on the left shows the location of stimulation electrodes for activating synaptic potentials at afferent and intrinsic synapses. On the right, the intracellularly recorded synaptic potentials are shown before and during perfusion with the cholinergic agonist carbachol. Synaptic potentials evoked by afferent fiber stimulation show no change in height during perfusion of carbachol. In contrast, synaptic potentials elicited by intrinsic fiber stimulation show a strong decrease during perfusion of carbachol. On the far right, traces are shown from a biophysical simulation of the piriform cortex, in which synaptic potentials are represented by dual exponential functions. This simulation used the GENESIS simulation package.