Changes in properties of lamprey reticulospinal neurons following spinal cord injury
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The lamprey is one of the most ancient vertebrates, sharing many of basic characteristics of the brain and spinal cord with higher, more evolved vertebrates such as mammals. However, unlike humans and other higher vertebrates, lampreys display robust axonal regeneration in the central nervous system following spinal cord injury (SCI). For instance, axons of reticulospinal (RS) neurons in the brain can regenerate and reconnect with spinal targets leading to recovery of locomotor behavior within a few weeks following SCI. During axonal regeneration, at ~2-3 weeks following SCI, injured RS neurons display dramatic changes in their electrical properties (i.e. "injury phenotype", absence of 2/3 afterpotentials) compared to uninjured neurons. These changes may be due to axonal injury itself, interruption of retrograde axonal transport, and/or changes in synaptic inputs. The present work will focus on several aspects of lamprey RS neurons following SCI. (1) Can activation of second messenger signaling pathways stimulate neurite outgrowth of lamprey RS neurons without altering their electrical properties? (2) Does axotomy affect Ca2+ and SK channels and their underlying conductances? (3) Are the changes in biophysical properties of RS neurons following SCI due, in part, to disruption of retrograde axonal transport? (4) Does SCI lead to changes in morphology and synaptic inputs of injured lamprey RS neurons? For lamprey RS neurons in culture, activation of cAMP pathways stimulated neurite outgrowth. In brainspinal cord preparations, forskolin resulted in action potential broadening, at least for uninjured RS neurons, which would very likely increase calcium influx. In contrast, for lamprey RS neurons, dbcAMP stimulated neurite outgrowth without altering their electrical properties. These results suggest that activation of cAMP signaling may be an effective approach for stimulating axonal regeneration of RS neurons following spinal cord injury. Our results suggest that there may be little differences in Ca2+ currents and SK currents between injured and uninjured large RS neurons. Perhaps the slight reduction in the total Ca2+ influx combined with a slight reduction of SK current (fewer activated by Ca2+) is responsible for the abolishment of the sAHP in lamprey RS neurons ~2-3 weeks following injury. In uninjured large RS neurons that were not physically damaged by the application of the microtubuledisrupting agent vinblastine, blocking retrograde axonal transport caused some neurons to fire erratically and display the "injury phenotype", which is typical for axotomized neurons following SCI. These results suggest that retrograde axonal transport may play an important role in the maintenance of normal electrical properties in uninjured lamprey large RS neurons. Additionally, these results suggest that following SCI, interruption of retrograde axonal transport perhaps contributes to the changes in electrical properties (i.e "injury phenotype") in injured lamprey RS neurons. Injured large RS neurons did not display significant differences in the amplitudes of their synaptic responses from stimulation of the oral hood compared to uninjured neurons whether they were stimulated contralaterally or ipsilaterally, and synaptic responses of injured and uninjured RS neurons from stimulations on either the right or the left side of the oral hood were not significantly different. Taken together, these results suggest that injury does not substantially alter the synaptic inputs of injured large RS neurons. Following rostral SCI in lampreys, large injured RS neurons did not display significant changes in their basic morphology of lamprey large RS neurons. For example, the major and minor diameters of injured large RS neurons were not significantly different than those of uninjured neurons. In addition, compared to uninjured neurons, injured neurons did not have different number of primary and secondary dendrites. These results suggest that SCI does not substantially alter the basic morphology of large lamprey RS neurons. The present work provided a better understanding of the mechanisms underlying the biophysical changes of injured lamprey RS neurons during axonal regeneration. These findings could help in the development of novel therapeutic strategies to enhance axonal regeneration, following spinal cord injury in higher vertebrates, including perhaps humans.