Serotonergic modulation of post-synaptic inhibition and locomotor alternating pattern in the spinal cord

Abstract

The central pattern generators (CPGs) for locomotion, located in the lumbar spinal cord, are functional at birth in the rat. Their maturation occurs during the last few days preceding birth, a period during which the first projections from the brainstem start to reach the lumbar enlargement of the spinal cord. Locomotor burst activity in the mature intact spinal cord alternates between flexor and extensor motoneurons through reciprocal inhibition and between left and right sides through commisural inhibitory interneurons. By contrast, all motor bursts are in phase in the fetus. The alternating pattern disappears after neonatal spinal cord transection which suppresses supraspinal influences upon the locomotor networks. This article will review the role of serotonin (5-HT), in particular 5-HT2 receptors, in shaping the alternating pattern. For instance, pharmacological activation of these receptors restores the left-right alternation after injury. Experiments aimed at either reducing the endogenous level of serotonin in the spinal cord or blocking the activation of 5-HT2 receptors. We then describe recent evidence that the action of 5-HT2 receptors is mediated, at least in part, through a modulation of chloride homeostasis. The postsynaptic action of GABA and glycine depends on the intracellular concentration of chloride ions which is regulated by a protein in the plasma membrane, the K+-Cl− cotransporter (KCC2) extruding both K+ and Cl− ions. Absence or reduction of KCC2 expression leads to a depolarizing action of GABA and glycine and a marked reduction in the strength of postsynaptic inhibition. This latter situation is observed early during development and in several pathological conditions, such as after spinal cord injury, thereby causing spasticity and chronic pain. It was recently shown that specific activation of 5-HT2A receptors is able to up-regulate KCC2, restore endogenous inhibition and reduce spasticity.

Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization

“…While this effect has been traditionally tied to a blockade of GABA-dependent neural inhibition, research examining the effect of SCI on spinal levels of KCC2 suggest an alternative interpretation—that administration of bicuculline fosters locomotor behavior because it reduces a GABA-dependent over-excitation that interferes with adaptive plasticity (Grau et al, 2014; Viemari et al, 2011). Here too, descending serotonergic fibers appear to play a key role (Gackiere and Vinay, 2014) and have been shown to impact KCC2 expression and the chloride equilibrium potential (Bos et al, 2013; Gackiere and Vinay, 2014). Our findings fit with an emerging view that suggests alterations in GABA function provide a form of ionic plasticity that regulates the capacity for neural modifications (Ferrini and De Koninck, 2013).…”

Serotonergic activation of locomotor behavior and posture in one-day old rats

“…Thus it would seem to suggest that the application of quipazine would differentially affect these interneurons, resulting in a decrease in the dose needed to evoke coordinated locomotor behavior in adult animals compared to neonates. Another important component of the 5-HT system is that 5-HT 2A seems to facilitate chloride homeostasis following spinal cord injury [36]. Following spinal injury, there is a disruption in chloride homeostasis, resulting in decreased inhibition.…”

“…Thus, less stimulation is needed to result in activity within neural populations. It has been demonstrated that application of a 5-HT 2A agonist will result in a shift back to pre-injury levels of inhibition [36], which suggests that dose differences among ages do not necessarily arise from disruption in chloride homeostasis. Additionally, following spinal injury there is an up-regulation of 5-HT receptors in the spinal cord [37, 38].…”

Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury

“…The serotonergic system modulates both nociceptive and motor spinal cord circuits, 28,31,32,39,45,52,57 and motor activity increases the release of serotonin within spinal and supraspinal areas parallel to reduction of mechanical hyperalgesia. 29,33 Moreover, physical exercise decreases NKCC1 levels and restores KCC2 along with recovery of inhibitory reflex responses in spinal cord injured rats.…”