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.
