Chondroitinase ABC promotes plasticity of spinal reflexes following peripheral nerve injury.
Peripheral nerve transection, even with optimal repair, can result in an extensive disruption of central connectivity, which can lead to long-lasting impairments in motor and sensory function. We hypothesised that removal of spinal cord chondroitin sulphate proteoglycans (CSPGs) would promote plasticity in the spinal cord, allowing compensation for inaccurate peripheral reinnervation. In adult rats, the median and radial nerves were cut and repaired, either correctly (median to median and radial to radial), or incorrectly (median to radial and vice versa). This produced two levels of inaccuracy of peripheral reinnervation. Whole nerve recordings from a third brachial plexus nerve, the ulnar, were made during median or radial nerve stimulation. Low and high threshold reflexes were characterised in uninjured animals and a clear difference in the pattern of ulnar response to flexor (median) or extensor (radial) stimulation was established. This included the phenomenon of wind-up, where repetitive median nerve stimulation at supramaximal C-fibre threshold leads to a progressive increase in the number of spikes recorded. To achieve digestion of CSPGs a lentiviral vector expressing ChABC was delivered to the spinal cord via intraspinal injection. Following ChABC treatment, we found several indicators of reorganisation of central connections. Firstly, we found that the amplitude of a low threshold, polysynaptic reflex could be increased after nerve injury, only following treatment with ChABC. Secondly, wind-up of motor responses in the ulnar nerve to supramaximal stimulation of afferents in the median nerve, which collapses after nerve injury (to ~25% of uninjured value), could be restored by ChABC after correct repair (to ~90% of uninjured value). Thirdly, wind-up in ulnar motor axons to stimulation of radial nerve afferents, which is minimal in the uninjured state, becomes significantly stronger after nerve injury and ChABC treatment (a 10 fold increase). We propose that application of a plasticity-promoting treatment to the spinal cord allows the amplification of adaptive changes in response to inaccurate wiring in the periphery.
Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London Bridge, SE1 1UL, UK. karen.bosch@kcl.ac.uk
Karen D
KD
Bosch
Elizabeth J
EJ
Bradbury
Joost
J
Verhaagen
James W
JW
Fawcett
Stephen B
SB
McMahon
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D019765:Chondroitin ABC Lyase / Q000235:genetics / Q000627:therapeutic use*; D004562:Electrocardiography; D055724:Electrophysiological Phenomena; D005822:Genetic Vectors; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000503:physiopathology*; D051381:Rats; D012023:Reflex, Monosynaptic / Q000187:drug effects*; D012026:Reflex, Stretch / Q000502:physiology; D012677:Sensation; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology*
D019765:Chondroitin ABC Lyase