Cholinergic Modulation of Spike Timing and Spike Frequency Adaptation in Neocortical Neurons

Abstract

Neocortical neurons in vivo are spontaneously active and intracellular recordings have revealed strongly fluctuating membrane potentials arising from the irregular arrival of excitatory and inhibitory synaptic potentials. In addition to these rapid fluctuations, more slowly changing influences from diffuse activation of neuromodulatory systems alter the excitability of cortical neurons by modulating a variety of potassium conductances. In particular, acetylcholine, which affects learning and memory, reduces the slow afterhyperpolarization, which contributes to spike frequency adaptation. We used whole cell patch clamp recordings of pyramidal neurons in neocortical slices and computational simulations to show, first, that when fluctuating inputs were added to a constant current pulse, spike frequency adaptation was reduced as the amplitude of the fluctuations was increased. High-frequency, high-amplitude fluctuating inputs that resembled in vivo conditions [1] elicited only weak spike frequency adaptation. Second, bath application of carbachol, a cholinergic agonist, significantly increased the firing rate in response to a fluctuating input but minimally displaced the spike times by less than 3 milliseconds, comparable to the spike jitter observed when a visual stimulus is repeated under in vivo conditions (see [2] for more details on experiments and simulations). These results suggest that cholinergic modulation may preserve information encoded in precise spike timing, but not in interspike intervals, and that cholinergic mechanisms other than those involving adaptation may contribute significantly to cholinergic modulation of learning and memory.