Canadian Institutes of Health Research Group in Sensory-Motor Systems

RE-ESTABLISHING CONNECTIONS LOST DUE TO SPINAL CORD INJURY: A ROLE FOR AXON-LIKE PROCESSES ORIGINATION FROM DENDRITES?

                The ultimate goal of research devoted to neurotrauma, especially injuries to the spinal cord, is to replace connections lost due to injury with new connections that ameloriate the dysfunction caused by the injury. A critical step towards reaching this goal is the successful regeneration of the injured axon. Since the pioneering studies of Aguayo and colleagues, there has been an intense effort to devise strategies that promote axon growth, either by overcoming growth inhibiting factors (eg. Nogo-A) or by augmenting growth promoting factors (eg. neurotrophins). This effort has led to the identification of numerous factors that are critical for the success or failure of regeneration of the injured axon.

                This research proposal is based on a different mechanism of axon regeneration. Unlike the studies described above, this mechanism does not involve regeneration of the original injured axon. Instead, it is founded on an unexpected ability of axotomized neurons in the adult mammalian nervous system to grow new axons that originate from their distal dendrites (MacDermid et al., 2000; Rose et al., 2001). We refer to this mechanism for regeneration as ‘Plan B’. However, the extent to which axons growing from distal dendrites can serve to replace lost connections remains largely untested. It is the long term goal of this research programme to address this question. 

Specific hypotheses and related objectives are:

1) Growth and guidance of axon-like processes emerging from distal dendrites of axotomized neck motoneurons are mediated by the cell adhesion molecule, L1.

2) Axon-like collaterals that emerge from the distal dendrites of axotomized neck motoneurons form synaptic connections.

     The experiments to address these hypotheses will exploit the results of our recent studies that demonstrate that axon-like processes, defined by molecular and anatomical criteria, emerge from distal dendrites of axotomized neck motoneurons (MacDermid et al., 2000; Rose et al., 2001).  These experiments have two objectives:

          A: To demonstrate that axon-like processes are immunoreactive for L1.

          B: To show that bouton-like swellings found on axon-like processes have ultrastructural   features typical of functional synapses and are immunoreactive for synaptophysin and P/Q   calcium  channels,  proteins that play key roles in the release of neurotransmitters.

3) Axon-like processes that emerge from the distal dendrites of axotomized spinal interneurons can re-establish connections that are lost due to the axotomy.

      The experiments to address these hypotheses will be based on a new injury paradigm in which the spinal cord at C3 is transected sagittally.  This injury is designed to sever the axons of commissural interneurons and provides a means of meeting the following objective:

      C: To show that axotomized commissural interneurons, via new axons that originate from    their distal dendrites, form synapses with dendrites of identified neck motoneurons in the     contralateral ventral horn.