Abstract
Cholinergic neuromodulation plays key roles in the regulation of neuronal excitability, network activity, arousal, and behavior. On longer time scales, cholinergic systems play essential roles in cortical development, maturation, and plasticity. Presumably, these processes are associated with substantial synaptic remodeling, yet to date, long-term relationships between cholinergic tone and synaptic remodeling remain largely unknown. Here we used automated microscopy combined with multielectrode array recordings to study long-term relationships between cholinergic tone, excitatory synapse remodeling, and network activity characteristics in networks of cortical neurons grown on multielectrode array substrates. Experimental elevations of cholinergic tone led to the abrupt suppression of episodic synchronous bursting activity (but not of general activity), followed by a gradual growth of excitatory synapses over hours. Subsequent blockage of cholinergic receptors led to an immediate restoration of synchronous bursting and the gradual reversal of synaptic growth. Neither synaptic growth nor downsizing was governed by multiplicative scaling rules. Instead, these occurred in a subset of synapses, irrespective of initial synaptic size. Synaptic growth seemed to depend on intrinsic network activity, but not on the degree to which bursting was suppressed. Intriguingly, sustained elevations of cholinergic tone were associated with a gradual recovery of synchronous bursting but not with a reversal of synaptic growth. These findings show that cholinergic tone can strongly affect synaptic remodeling and synchronous bursting activity, but do not support a strict coupling between the two. Finally, the reemergence of synchronous bursting in the presence of elevated cholinergic tone indicates that the capacity of cholinergic neuromodulation to indefinitely suppress synchronous bursting might be inherently limited.
Highlights
Cholinergic neuromodulation plays key roles in processes observable at levels ranging from cellular biophysics to behavior, and on time scales ranging from sub-seconds to circadian rhythms
We describe the use of such a system [30] to address the following questions: How is synaptic remodeling affected over long time scales by experimental manipulations of cholinergic tone? How are network activity characteristics affected by these manipulations in the same preparations? How do these manipulations affect the rules that govern synaptic remodeling? How are cholinergic-induced changes in synaptic remodeling related to cholinergic-induced changes in network activity properties?
Carbachol Application Drives Synaptic Growth In the present study we examined long-term relationships between cholinergic tone and the remodeling of glutamatergic synapses, the most common type of excitatory synapse in the mammalian CNS
Summary
Cholinergic neuromodulation plays key roles in processes observable at levels ranging from cellular biophysics to behavior, and on time scales ranging from sub-seconds to circadian rhythms. Lesions of cholinergic afferents (mainly from the basal forebrain) have been shown to delay cortical neuronal development, alter cortical cytoarchitecture [12], and suppress cortical map plasticity associated with various sensory deprivation paradigms [13], in particular, forms of cortical plasticity driven by behavioral experience [14]. These large scale changes in cortical connectivity are associated with substantial synaptic remodeling, yet to date, relationships between slow changes in cholinergic tone and synaptic remodeling remain largely unknown
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