Muscle paralysis after spinal cord injury is partly caused by a loss of brainstem-derived serotonin (5-HT), which normally maintains motoneuron excitability by regulating crucial persistent calcium currents. Here we examine how over time motoneurons compensate for lost 5-HT to regain excitability. We find that, months after a spinal transection in rats, changes in post-transcriptional editing of 5-HT2C receptor mRNA lead to increased expression of 5-HT2C receptor isoforms that are spontaneously active (constitutively active) without 5-HT. Such constitutive receptor activity restores large persistent calcium currents in motoneurons in the absence of 5-HT. We show that this helps motoneurons recover their ability to produce sustained muscle contractions and ultimately enables recovery of motor functions such as locomotion. However, without regulation from the brain, these sustained contractions can also cause debilitating muscle spasms. Accordingly, blocking constitutively active 5-HT2C receptors with SB206553 or cyproheptadine, in both rats and humans, largely eliminates these calcium currents and muscle spasms, providing a new rationale for antispastic drug therapy.

Freezing of gait (FoG) is an episodic, brief inability to step that delays gait initiation or interrupts ongoing gait. FoG is often associated with an alternating shaking of the knees, clinically referred to as knee trembling or trembling in place. The pathophysiology of FoG and of the concomitant trembling knees is unknown; impaired postural adjustment in preparation for stepping is one hypothesis. We examined anticipatory postural adjustments (APAs) prior to protective steps induced by a forward loss of balance in 10 Parkinson’s disease (PD) subjects with marked FoG and in 10 control subjects. The amplitude and timing of the APAs were determined from changes in the vertical ground-reaction forces recorded by a force plate under each foot and were confirmed by electromyographic recordings of bilateral medial gastrocnemius, tibialis anterior and tensor fascia latae muscles. Protective steps were accomplished with a single APA followed by a step for control subjects, whereas PD subjects frequently exhibited multiple, alternating APAs coexistent with the knee trembling commonly observed during FoG as well as delayed, inadequate or no stepping. These multiple APAs were not delayed in onset and were of similar or larger amplitude than the single APAs exhibited by the control subjects. These observations suggest that multiple APAs produce the knee trembling commonly associated with FoG and that FoG associated with a forward loss of balance is caused by an inability to couple a normal APA to the stepping motor pattern.

1. Intracellular recording from medial gastrocnemius (MG) motoneurones was used to examine postsynaptic potentials produced by electrical stimulation of the plantaris nerve at group I strength at rest and during fictive locomotion.

No abstract

Blood vessels in the central nervous system (CNS) are controlled by neuronal activity; for example, widespread vessel constriction (vessel tone) is induced by brainstem neurons that release the monoamines serotonin and noradrenaline, and local vessel dilation is induced by glutamatergic neuron activity. Here, we examined how vessel tone adapts to the loss of neuron-derived monoamines after spinal cord injury (SCI) in rats. We find that, months after the imposition of SCI, the spinal cord below the site of injury is in a chronic state of hypoxia, due to paradoxical excess activity of monoamine receptors (5-HT1) on pericytes, despite the absence of monoamines. This monoamine receptor activity causes pericytes to locally constrict capillaries, reducing blood flow to ischemic levels. Receptor activation in the absence of monoamines results from the production of trace amines (such as tryptamine) by pericytes that ectopically express the enzyme aromatic-l-amino-acid-decarboxylase (AADC), which synthesizes trace amines directly from dietary amino acids (such as tryptophan). Inhibition of monoamine receptors or of AADC, or even increased inhaled oxygen, produces substantial relief from hypoxia and improves motoneuron and locomotor function after SCI.

Immediately after spinal cord injury (SCI), a devastating paralysis results from the loss of brain stem and cortical innervation of spinal neurons that control movement, including a loss of serotonergic (5-HT) innervation of motoneurons. Over time, motoneurons recover from denervation and function autonomously, exhibiting large persistent calcium currents (Ca PICs) that both help with functional recovery and contribute to uncontrolled muscle spasms. Here we systematically evaluated which 5-HT receptor subtypes influence PICs and spasms after injury. Spasms were quantified by recording the long-lasting reflexes (LLRs) on ventral roots in response to dorsal root stimulation, in the chronic spinal rat, in vitro. Ca PICs were quantified by intracellular recording in synaptically isolated motoneurons. Application of agonists selective to 5-HT(2B) and 5-HT(2C) receptors (including BW723C86) significantly increased the LLRs and associated Ca PICs, whereas application of agonists to 5-HT(1), 5-HT(2A), 5-HT(3), or 5-HT(4/5/6/7) receptors (e.g., 8-OH-DPAT) did not. The 5-HT(2) receptor agonist-induced increases in LLRs were dose dependent, with doses for 50% effects (EC(50)) highly correlated with published doses for agonist receptor binding (K(i)) at 5-HT(2B) and 5-HT(2C) receptors. Application of selective antagonists to 5-HT(2B) (e.g., RS127445) and 5-HT(2C) (SB242084) receptors inhibited the agonist-induced increase in LLR. However, antagonists that are known to specifically be neutral antagonists at 5-HT(2B/C) receptors (e.g., RS127445) had no effect when given by themselves, indicating that these receptors were not activated by residual 5-HT in the spinal cord. In contrast, inverse agonists (such as SB206553) that block constitutive activity at 5-HT(2B) or 5-HT(2C) receptors markedly reduced the LLRs, indicating the presence of constitutive activity in these receptors. 5-HT(2B) or 5-HT(2C) receptors were confirmed to be on motoneurons by immunolabeling. In summary, 5-HT(2B) and 5-HT(2C) receptors on motoneurons become constitutively active after injury and ultimately contribute to recovery of motoneuron function and emergence of spasms.

Movement and posture depend on sensory feedback that is regulated by specialized GABAergic neurons (GAD2 + ) that form axo-axonic contacts onto myelinated proprioceptive sensory axons and are thought to be inhibitory. However, we report here that activating GAD2 + neurons, directly with optogenetics or indirectly by cutaneous stimulation, facilitates sensory feedback to motoneurons in awake rodents and humans. GABAA receptors and GAD2 + contacts adjacent to nodes of Ranvier at branch points of sensory axons cause this facilitation, preventing spike propagation failure that is otherwise common without GABA. GABAA receptors are generally lacking from axon terminals (unlike GABAB) and do not inhibit transmitter release onto motoneurons, disproving the long-standing assumption that GABAA receptors cause presynaptic inhibition. GABAergic innervation of nodes near branch points allows individual branches to function autonomously, with GAD2 + neurons regulating which branches conduct, adding a computational layer to the neuronal networks generating movement and likely generalizing to other CNS axons. MainThe ease with which animals move defies the complexity of the underlying neuronal circuits, which include corticospinal tracts (CSTs) that coordinate skilled movement, spinal interneurons that form central patterns generators (CGPs) for walking, and motoneurons that ultimately drive the muscles 1 .Sensory feedback ensures the final precision of such motor acts, with proprioceptive feedback to motoneurons producing a major part of the muscle activity in routine movement and posture 2-4 , without which severe ataxia occurs 5 . Proprioceptive sensory feedback is regulated by specialized GABAergic neurons (GAD2 + ; abbreviated GABAaxo neurons) that form axo-axonic connections onto the sensory axon terminals [6][7][8] . These neurons are thought to produce presynaptic inhibition of sensory feedback to motoneurons 9-11 and possibly limit inappropriate sensory feedback 3,4,7 . However, during movement the CST, CPG and even sensory neurons all augment GABAaxo neuron activity [11][12][13][14][15][16] right at a time when sensory feedback is known to be increased to ensure precision and postural stability 2-4 , raising the question of whether GABAaxo neurons have a yet undescribed excitatory action.The long-standing view that GABAergic neurons produce presynaptic inhibition of proprioceptive sensory axon terminals in adult mammals actually lacks direct evidence, largely because of the difficulty in recording from these small terminals and the technical limitations of previously employed

Stepping responses were studied in infants between the ages of 10 days and 10 months while they were supported to step on a slowly moving treadmill belt. Surface electromyography (EMG) from muscles in the lower limb, force exerted by the feet on the treadmill belt, and the motion of the lower limbs were recorded. Two groups of infants were studied, those who had a small amount of daily practice in stepping and those who did not. Practice resulted in a dramatic increase in the incidence of stepping recorded in the laboratory, particularly for the periods between 1 and 6 months of age. The majority of infants showed clear alternation between the flexor and extensor muscles during walking, regardless of age. Co‐contraction between flexors and extensors, estimated by the overlap in area between rectified and smoothed EMG from a muscle pair, was greater for some muscle groups in the infant compared with the adult. Practice resulted in a significantly lower co‐contraction index for the tibialis anterior‐ quadriceps muscle pair. Practice did not affect the mean step cycle duration. Infants of all ages could step at a range of treadmill speeds by adjusting their step cycle duration. The relationship between the treadmill speed and cycle duration was well fitted by a power function, similar to those reported for intact cats and adult humans. The change in step cycle duration resulted almost entirely from a change in the extensor burst duration, whereas the flexor burst duration remained constant. Airstepping could be elicited in some infants. The cycle durations for airstepping were close to the shortest cycles recorded on the treadmill. In conclusion, the system for generating rhythmic, alternating activity of the lower limbs for stepping is clearly developed by birth. The stepping is sustained and regular, particularly if stepping practice is incorporated briefly each day. The infant population provides a good subject pool for studying the afferent control of walking in the human, before cerebral influences are fully developed. The characteristics and maturity of the system remain to be determined.