Retracing your footsteps: developmental insights to spinal network plasticity following injury

Abstract

During development of the spinal cord, a precise interaction occurs between descending projections and sensory afferents, with spinal networks that lead to expression of coordinated motor output. In the rodent, during the last embryonic week, motor output first occurs as regular bursts of spontaneous activity, progressing to stochastic patterns of episodes that express bouts of coordinated rhythmic activity perinatally. Locomotor activity becomes functionally mature in the 2nd postnatal wk and is heralded by the onset of weight-bearing locomotion on the 8th and 9th postnatal day. Concomitantly, there is a maturation of intrinsic properties and key conductances mediating plateau potentials. In this review, we discuss spinal neuronal excitability, descending modulation, and afferent modulation in the developing rodent spinal cord. In the adult, plastic mechanisms are much more constrained but become more permissive following neurotrauma, such as spinal cord injury. We discuss parallel mechanisms that contribute to maturation of network function during development to mechanisms of pathological plasticity that contribute to aberrant motor patterns, such as spasticity and clonus, which emerge following central injury.

Keywords: development; injury; network function; pathology; spinal cord.

Fig. 1.

Changes in motoneuron intrinsic properties during development and following injury. Motoneurons undergo several changes during development from (A) perinatal to juvenile to adulthood, which influence their intrinsic excitability. B: somata become larger and dendritic arbor more dispersed during development, which decreases following injury. C: increases in KCC2 (blue) reduce intracellular chloride (Cl⁻) concentration (green), causing GABA/glycine transmission to become functionally inhibitory. D: action potentials recorded from motoneurons (MN; E) become narrower over the 1st wk, contributing, in part, to (F) enhanced, repetitive firing capabilities.

Fig. 2.

Parallel changes occur in descending and sensory afferents of lumbar spinal cord during development and following injury. A: at peri- and postnatal stages, there is an increase in descending innervation of the lumbar spinal cord from the brain (key events are in bold). The emergence of alternating rhythmic motor patterns coincides with the first appearance of 5-HT fibers in the lumbar spinal cord (E18) and the emergence of weight bearing with the development of PICs in motoneurons (MNs) and corticospinal tract (CST) fibers in the lumbar gray matter (P9). Subsequent loss of descending inputs to the lumbar spinal cord following injury result in postural and locomotor deficits and the emergence of pathological movements due to constitutive 5-HT and NA receptor activity, increased PICs, and downregulation of KCC2 expression. B: figure summarizing data from Chakrabarty and Martin (2011b), Mentis et al. (2006), Siembab et al. (2016), and Smith et al. (2017), illustrating the postnatal refinement of synaptic sensory inputs and increased inputs from motoneuron collaterals to Renshaw cells (RC) from birth to adulthood, which revert following SCI. This developmental retraction of afferent inputs from lumbar spinal cord cell types is dependent on the presence of descending pathways. These data highlight the codependency of sensory and descending pathways in contributing to normal spinal circuitry formation during development, which becomes reversed in adults following SCI.