Spinal cholinergic interneurons regulate the excitability of motoneurons during locomotion

Abstract

To effect movement, motoneurons must respond appropriately to motor commands. Their responsiveness to these inputs, or excitability, is regulated by neuromodulators. Possible sources of modulation include the abundant cholinergic ''C boutons'' that surround motoneuron somata. In the present study, recordings from motoneurons in spinal cord slices demonstrated that cholinergic activation of m 2-type muscarinic receptors increases excitability by reducing the action potential afterhyperpolarization. Analyses of isolated spinal cord preparations in which fictive locomotion was elicited demonstrated that endogenous cholinergic inputs increase motoneuron excitability during locomotion. Anatomical data indicate that C boutons originate from a discrete group of interneurons lateral to the central canal, the medial partition neurons. These results highlight a unique component of spinal motor networks that is critical in ensuring that sufficient output is generated by motoneurons to drive motor behavior.T o generate movement, it is necessary for motoneurons (MNs) to integrate the inputs (motor commands) they receive and produce an output sufficient to effect muscular contraction. The relationship of input to output is determined by neuronal excitability, which in the case of MNs is known to be regulated by identified descending modulatory systems (1). Given that these descending systems are disrupted after spinal cord injury, strategies aimed at restoring movement need to address not only premotor circuits that provide motor commands but also any modulatory systems that ensure MNs are sufficiently excitable to respond to these commands. Spinal premotor circuits for locomotion can be activated after spinal transection (2) and provide one clear target for treatments designed to produce functional recovery. Should an intrinsic spinal modulatory system exist, this would be an important additional target for such strategies.The somata and proximal dendrites of MNs are contacted by large cholinergic varicosities named ''C boutons'' (3-11). It has been known since 1972 (12) that C boutons originate from spinal cord neurons, but the location of these cells remains unknown (10). Although the C bouton synapse has been anatomically characterized and shown to be associated with postsynaptic type 2 muscarinic (m 2 ) receptors (8-10), neither the physiological effects of m 2 receptor activation on MNs nor the roles of C boutons in motor activity are known. In the absence of motor behavior, exogenous application of cholinergic agonists affects MN excitability via undefined mechanisms (13-17). We therefore studied the possibility that the intrinsic spinal neurons that give rise to the C boutons regulate MN excitability via activation of m 2 receptors, and that this system is used during motor behavior. ResultsThe Effects of Muscarinic Receptor Activation on Spinal MNs. Because C boutons are closely associated with postsynaptic m 2 receptors by the second postnatal week (8-10), we investigated the effects of muscarinic receptor activatio...

Glial Scar Expression of CHL1, the Close Homolog of the Adhesion Molecule L1, Limits Recovery after Spinal Cord Injury

“…Still, they suggest that the degree of preservation and reestablishment of the modulatory cholinergic input to motoneuron somata, considerably reduced after spinal cord lesion, may be essential for motor recovery. This notion is supported by recent electrophysiological data showing that, in the intact spinal cord, the cholinergic perisomatic synapses regulate motoneuron excitability during locomotion (Miles et al, 2007). In addition to plantar stepping, improved walking in CHL1-deficient mice was documented by the rump-height index, a parameter estimating the abilities for coordinated and rhythmic activation of muscles working at different joints.…”

Serotonin Affects Movement Gain Control in the Spinal Cord

“…Conversely, the MVC is still unaffected when the 5-HT efficacy is reduced by a selective 5-HT reuptake inhibitor. We postulate in this case that other neuromodulators help in amplifying the gain when large force production is demanded, as revealed by single-cell studies (Miles et al, 2007;Power et al, 2010). Thus, this result is consistent with the notion that other neuromodulators might also play a role in gain control.…”

“…There are many previously described changes in excitability of the human motor system. An intensive volitional contraction will result in reflex potentiation in both the contracting (Enoka et al, 1980;Gregory et al, 1990) and remote (Delwaide and Toulouse, 1981;Dowman and Wolpaw, 1988;Miyahara et al, 1996;Zehr and Stein, 1999;Stam, 2000) muscles, as well as an enhancement of corticospinal tract excitability (Kawakita et al, 1991;Péréon et al, 1995;Stedman et al, 1998;Boroojerdi et al, 2000;Tazoe et al, 2009). The proposed mechanisms underlying this remote alteration in the excitability of the motor system range from decreased presynaptic inhibition of Ia terminals to widespread increases in cortical excitability.…”

Changes in Motoneuron Properties and Synaptic Inputs Related to Step Training after Spinal Cord Transection in Rats

“…Alternatively, it is possible that not all serotonergic influence is lost after transection (Clineschmidt et al, 1971;Hadjiconstantinou et al, 1984;Newton et al, 1986;Newton and Hamill, 1988) and that training somehow influences these inputs, or that other neurotransmitter systems play a role in AHP modulation (Schotland et al, 1995). Recently, Miles et al (2007) have demonstrated that muscarinic receptors on motoneurons are activated by cholinergic C-type synaptic boutons, and this reduces AHP amplitude. Reduction of C-type bouton activity after transection with an increase after training could contribute to the findings reported here.…”