Changes in functional properties and 5-HT modulation above and below a spinal transection in lamprey

Abstract

In addition to the disruption of neural function below spinal cord injuries (SCI), there also can be changes in neuronal properties above and below the lesion site. The relevance of these changes is generally unclear, but they must be understood if we are to provide rational interventions. Pharmacological approaches to improving locomotor function have been studied extensively, but it is still unclear what constitutes an optimal approach. Here, we have used the lamprey to compare the modulatory effects of 5-HT and lesion-induced changes in cellular and synaptic properties in unlesioned and lesioned animals. While analyses typically focus on the sub-lesion spinal cord, we have also examined effects above the lesion to see if there are changes here that could potentially contribute to the functional recovery. Cellular and synaptic properties differed in unlesioned and lesioned spinal cords and above and below the lesion site. The cellular and synaptic modulatory effects of 5-HT also differed in lesioned and unlesioned animals, again in region-specific ways above and below the lesion site. A role for 5-HT in promoting recovery was suggested by the potential for improvement in locomotor activity when 5-HT was applied to poorly recovered animals, and by the consistent failure of animals to recover when they were incubated in PCPA to deplete 5-HT. However, PCPA did not affect swimming in animals that had already recovered, suggesting a difference in 5-HT effects after lesioning. These results show changes in 5-HT modulation and cellular and synaptic properties after recovery from a spinal cord transection. Importantly, effects are not confined to the sub-lesion spinal cord but also occur above the lesion site. This suggests that the changes may not simply reflect compensatory responses to the loss of descending inputs, but reflect the need for co-ordinated changes above and below the lesion site. The changes in modulatory effects should be considered in pharmacological approaches to functional recovery, as assumptions based on effects in the unlesioned spinal cord may not be justified.

Anatomical recovery of the spinal glutamatergic system following a complete spinal cord injury in lampreys

“…Our study provides an accessible model system to decipher the molecular mechanisms underlying glutamatergic spinal circuit remodelling and regeneration and how these processes could be optimized for therapeutic interventions in mammals. Further, this work stresses the importance of studying the changes above the injury and not only below, as suggested before by other authors47 and also the necessity of increasing our understanding of the spinal circuits not only in lesioned but also in un-lesioned animals4849.…”

The Lesioned Spinal Cord Is a “New” Spinal Cord: Evidence from Functional Changes after Spinal Injury in Lamprey

“…Data is presented as a boxplot to indicate the variability. Data from Cooke and Parker (2009) and Becker and Parker (2015) . No permission is required to reproduce this material.…”

“…The mechanism underlying this effect is unknown. It does not seem to reflect an L-type calcium, persistent sodium, or NMDA conductance (see Li et al, 2004a ), increased EPSP summation due to changes in half-width, or the recruitment of polysynaptic inputs ( Cooke and Parker, 2009 ; Becker and Parker, 2015 ). One possibility is that it reflects “synaptic drag” ( Martin and Pilar, 1964 ), an increase in asynchronous vesicle release that can cause slowly developing depolarizations with repetitive stimulation ( Hjelmstad, 2005 ; Iremonger and Bains, 2007 ).…”

Serotonin inhibits axonal regeneration of identifiable descending neurons after a complete spinal cord injury in lampreys

“…This indicates that serotonin could also be a target of interest in nonregenerating mammalian models of SCI since it can modulate several aspects of the regenerative process. Even more importantly the effects of serotonin revealed in these studies should be taken into account by those authors performing pharmacological treatments with serotonergic drugs to modulate spinal cord circuits and aiming to promote locomotor recovery after SCI (see 46 ), mainly because these treatments could be affecting the regeneration of new neurons or the re-growth of axotomized axons as shown here.…”

“…We assumed that these drugs also crossed the blood brain barrier in lampreys as in mammals, since the blood brain barrier of lampreys is similar to that of higher vertebrates 48,49 . Serotonin was applied at the same concentration previously used by other authors 46 . Becker and Parker 46 already reported that this concentration of serotonin affects the swimming behaviour of lesioned and unlesioned animals indicating that this application route also allows access to the CNS.…”