Synaptic Bombardment Modulates Muscarinic Effects in Forelimb Motor Cortex

Abstract

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.

Cholinergic filtering in the recurrent excitatory microcircuit of cortical layer 4

“…The ACH-induced persistent hyperpolarization described here is in marked contrast to the ACH-induced persistent depolarization previously demonstrated in identified neocortical PCs (9)(10)(11)(12). Therefore, it is likely that this type of response is a unique feature of L4-SNs.…”

“…In previous studies in rodents, a persistent hyperpolarization in response to ACH has only been observed in a few subpopulations of inhibitory neurons of the hippocampus and neocortex (30)(31)(32) as well as in extracortical regions of the CNS or in the PNS (33)(34)(35). In the neocortex, application of ACH has been reported to invariably induce a persistent depolarization in identified excitatory neurons (9)(10)(11)(12).…”

“…These studies showed that ACH invariably induces a persistent increase in the excitability of pyramidal cells (PCs) through activation of postsynaptic muscarinic ACH receptors (mACHRs) (9)(10)(11)(12), even though in 2 particular experimental conditions (10,12) puff applications of ACH evoke a transient (Ϸ1 s) hyperpolarization preceding or superimposed on a persistent depolarization. Neocortical nicotinic ACHRs mainly found on axon terminals have been shown to enhance synaptic transmission (13).…”

Focusing Effect of Acetylcholine on Neuroplasticity in the Human Motor Cortex

“…Thus it is probable that synapses that are globally modified by tDCS in the present study are more susceptible to cholinergic suppression of synaptic transmission during plasticity induction. A similar effect is also demonstrated by a recent study using a dynamic clamp system to mimic in-vivo-like background activities in motor cortical slices, in which cholinergic facilitation of LTP was attenuated in the presence of random background noise (Desai and Walcott, 2006).…”

Synaptic and Intrinsic Balancing during Postnatal Development in Rat Pups Exposed to Valproic Acidin Utero

“…Brain slices were prepared and electrophysiological recordings made essentially as previously described (Desai and Walcott, 2006;. Briefly, coronal sections of 350 m thickness containing medial prefrontal cortex were cut on a vibratome in ice-cold artificial CSF (ACSF) containing the following (in mM): 126 NaCl, 3 KCl, 1 NaH 2 PO 4 , 25 NaHCO 3 , 2 MgCl 2 , 2 CaCl 2 , and 25 dextrose.…”