Synaptic bombardment modulates muscarinic effects in forelimb motor cortex.

Neocortical neurons in vivo exist in an environment of continuous synaptic bombardment, receiving a complex barrage of excitatory and inhibitory inputs. This background activity (by depolarizing neurons, increasing membrane conductance, and introducing fluctuations) strongly alters many aspects of neuronal responsiveness. In this study, we asked how it shapes neuromodulation of postsynaptic responses. Specifically, we examined muscarinic modulation of forelimb motor cortex, a brain area in which cholinergic stimulation is known to be necessary for modifications during motor skill learning. Using a dynamic clamp system to inject simulated conductances into pyramidal neurons in motor cortical slices, we mimicked in vivo-like activity by introducing a random background of excitatory and inhibitory inputs. When muscarinic receptors were stimulated with the agonist oxotremorine-M, several previously described currents were modified, and excitability was increased. However, the presence of the background conductances strongly attenuated most muscarinic agonist effects, with the notable exception that sustained firing responses to trains of inputs were well preserved. This may be important for promoting plasticity in vivo.