Swimming against the tide: investigations of the C-bouton synapse

Abstract

C-boutons are important cholinergic modulatory loci for state-dependent alterations in motoneuron firing rate. m2 receptors are concentrated postsynaptic to C-boutons, and m2 receptor activation increases motoneuron excitability by reducing the action potential afterhyperpolarization. Here, using an intensive review of the current literature as well as data from our laboratory, we illustrate that C-bouton postsynaptic sites comprise a unique structural/functional domain containing appropriate cellular machinery (a “signaling ensemble”) for cholinergic regulation of outward K+ currents. Moreover, synaptic reorganization at these critical sites has been observed in a variety of pathologic states. Yet despite recent advances, there are still great challenges for understanding the role of C-bouton regulation and dysregulation in human health and disease. The development of new therapeutic interventions for devastating neurological conditions will rely on a complete understanding of the molecular mechanisms that underlie these complex synapses. Therefore, to close this review, we propose a comprehensive hypothetical mechanism for the cholinergic modification of α-MN excitability at C-bouton synapses, based on findings in several well-characterized neuronal systems.

Neuregulin 1-ErbB module in C-bouton synapses on somatic motor neurons: molecular compartmentation and response to peripheral nerve injury

“…With the emergence of new data about the C-bouton structure and function, and its possible relevance to MN pathology, there has been considerable recent interest in this type of synapses1948. Here, we extend our previous report showing that the NRG1-ErbB2/3 signalling module is expressed at C-boutons18, by providing a more detailed analysis of the compartmentation of these molecules and their relation with other proteins that are known to be specifically clustered at this synaptic site.…”

“…We have also demonstrated that ErbB2 and ErbB4 receptors are present in the presynaptic compartment, suggesting that NRG1 acts as a retrograde signalling molecule in C-type synapses. C-boutons are scarcely investigated structures19, which have been reported to suffer plastic changes in sick MNs after spinal cord injury2021, peripheral nerve lesion22, and amyotrophic lateral sclerosis (ALS)1823242526272829. In addition, mutations in S1R are considered risk factors for familial ALS, and abnormal accumulations of this protein in C-terminals have also been observed in patients with sporadic ALS303132.…”

A molecular rheostat: Kv2.1 currents maintain or suppress repetitive firing in motoneurons

“…; Deardorff et al . ). We next analysed action potential waveform parameters during repetitive firing for evidence of Na + channel inactivation.…”

“…; Liu & Bean, ) and on their precise subcellular somato‐dendritic localization (Muennich & Fyffe, ; Deardorff et al . ). Kv2 subunits, in particular, are widely expressed throughout the mammalian brain and spinal cord (Trimmer, ; Scannevin et al .…”

“…In mammalian lumbar spinal motoneurons (MNs), Kv2.1 channels form distinct clusters associated with highly regulated signalling ensembles at C‐bouton synapses on the soma and proximal dendrites (Muennich & Fyffe, ; Deardorff et al . , ; Romer et al . ).…”