In the lamprey following spinal lesion-mediated interruption of long axonal projections of reticulospinal (RS) neurons, sensory stimulation still elicited relatively normal locomotor muscle burst activity, but with some coordination deficits. Computer models incorporating the spinal lesions could mimic many aspects of the experimental results. Thus, after disruption of long-axon projections from RS neurons in the lamprey, descending propriospinal (PS) neurons appear to be a viable compensatory mechanism for indirect activation of spinal locomotor networks.

No abstract

Following spinal cord injury (SCI) for larval lampreys, descending axons of reticulospinal (RS) neurons regenerate, and locomotor function gradually recovers. In the present study, the electrophysiological properties of uninjured (left)-injured (right) pairs of large, identified RS neurons were compared following rostral, right spinal cord hemi-transections (HTs). First, changes in firing patterns of injured RS neurons began in as little as 2–3 days following injury, these changes were maximal at ~2–3 weeks (wks), and by 12–16 wks normal firing patterns were restored for the majority of neurons. Second, at ~2–3 wks following spinal cord HTs, injured RS neurons displayed several significant changes in properties compared to uninjured neurons: (a) more hyperpolarized VREST; (b) longer membrane time constant and larger membrane capacitance; (c) increased voltage and current thresholds for action potentials (APs); (d) larger amplitudes and durations for APs; (e) higher slope for the repolarizing phase of APs; (f) virtual absence of some afterpotential components, including the slow afterhyperpolarization (sAHP); (g) altered, injury-type firing patterns; and (h) reduced average and peak firing (spiking) frequencies during applied depolarizing currents. These altered properties, referred to as the “injury phenotype”, reduced excitability and spiking frequencies of injured RS neurons compared to uninjured neurons. Third, artificially injecting a current to add a sAHP waveform following APs for injured neurons or removing the sAHP following APs for uninjured neurons did not convert these neurons to normal firing patterns or injury-type firing patterns, respectively. Fourth, trigeminal sensory-evoked synaptic responses recorded from uninjured and injured pairs of RS neurons were not significantly different. Following SCI, injured lamprey RS neurons displayed several dramatic changes in their biophysical properties that are expected to reduce calcium influx and provide supportive intracellular conditions for axonal regeneration.

Following a severe spinal cord injury (SCI), the descending axons of reticulospinal (RS) neurons are damaged, resulting in paralysis below the site of the injury. For higher vertebrates, including humans, RS neurons are unable to regenerate their axons through the spinal lesion, resulting in permanent loss of voluntary motor control below the site of the injury. Conversely, some lower vertebrates, such as the lamprey, posses the remarkable ability to restore locomotor behavior below the site of the injury within weeks. This is possible because the central nervous system of the lamprey is a permissive environment for regeneration, and the injured RS neurons undergodramatic changes that are collectively referred to as the "injury phenotype" The present study investigated several mechanisms that might contribute to the injury phenotype. First, for injured lamprey RS neurons, a delayed membrane repolarization was activated at depolarizing potentials just below as well as above threshold, while for uninjured RS neurons the repolarization was mostly absent below threshold. Current and voltage clamp experiments were preformed to characterize the current mediating the delayed repolarization, as well as to estimate the effective activation voltage of these channels for injured and uninjured RS neurons. Additionally, pharmacology experiments indicated that the delayed membrane repolarization was significantly reduced in the presence of voltage-gated potassium channel blockers, and thus following SCI, there might be an up-regulation of outward rectifying potassium channels for injured lamprey RS neurons to reduce excitability. Second, for injured RS neurons, it appears that voltage-gated sodium channels are also up-regulated, but to a lesser degree than the voltage-gated potassium channels. This was tested by applying low doses of TTX to uninjured RS neurons to partially block voltage-gated sodium channels to experimentally simulate a differential increase in conductance for voltage-gated potassium channels. Applying low doses of TTX converted uninjured RS neurons from displaying normal biophysical properties, to displaying aspects of the "injury phenotype" such as altered firing properties and membrane resonance. Together, these possible neuronal changes account for many components of the "injury phenotype" seen in individual action potentials, as well as in repetitive firing. Understanding the neuronal changes that mediate the injury phenotype is critical, because these changes presumably create a cellular environment supportive for robust axonal regeneration. This and other knowledge will be critical for developing therapies to promote axonal regeneration and treat SCI in higher vertebrates, including hopefully one day, humans.