Improving sensorimotor deficits after spinal cord injury with peripheral Neurotrophin-3

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Traumatic spinal cord injuries (SCI) leave people with life changing disabilities including paralysis. There is a high probability that the circuitry below the injury responds in a maladaptive manner, hindering recovery and generating spasticity (i.e., abnormal processing of proprioceptive input called hyperreflexia and involuntary muscle activation).

A treatment which normalised proprioceptive changes after injury would be beneficial. The growth factor Neurotrophin-3 (NT3) is essential for the survival of proprioceptive neurons and their wiring-up during development. Experimentally induced elevation in adulthood can recover sensorimotor function following SCI in animal models. Work from our lab previously showed that an adeno-associated viral vector (AAV) encoding NT3 injected into affected muscles reduced hyperreflexia and restored sensorimotor function after bilateral corticospinal tract lesion in rats. Studies by other groups describe models of spasticity resulting from different thoracic spinal cord injuries (including clinically relevant contusion), and one of these groups described benefits of AAV-NT3 injections into hindlimb muscles.

The three studies comprising this thesis built on that work by testing intramuscular injections of AAV1-NT3 in two different clinically relevant SCI models in rats. In the first experiment, a C5-C6 bilateral 225 kDyn cervical contusion resulted in sustained excess of flexion over extension in forepaws and digits. The first characterisation of hyperreflexia as it develops in proprioceptive forepaw circuitry is provided. In the second experiment, rats underwent contusion of the cervical spinal cord to impair forelimb function. AAV-NT3 treatment of forelimb muscles induced transient recovery in pellet reaching but not in other forelimb related tasks. Hyperreflexia in a treated forelimb muscle was not reduced with treatment. Lesion volume quantification with ex vivo MRI found evidence of smaller lesions in the NT3 group. The final study used a model known to generate spontaneous hindlimb spasms, 250 kDyn contusion to T8, to assess NT3 mediated recovery of hindlimb function. Spasms were not reliably induced although left right hindlimb alternation during swimming was restored with treatment. NT3 treatment to hindlimb and abdominal muscles consistently elevated serum levels and reduced slips during ladder walking.
No evidence of hyperreflexia in the hindpaw was detected however vGlut1 positive boutons from proprioceptive afferents onto treated hindlimb α-motor neurons were reduced towards normal levels.

Ultimately this thesis revealed that AAV-NT3 treatment reorganised afferent terminals and modestly recovered aspects of forelimb and hindlimb function after contusive SCI, and that there is a need for more reliable models of spasms and hyperreflexia following SCI.
Date of Award1 May 2022
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorLawrence Moon (Supervisor)

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