Abstract
Strategies to induce recovery from lesions of the spinal cord have not fully resulted in clinical applications. This is a consequence of a number of impediments that axons encounter when trying to regrow beyond the lesion site, and that intraspinal rearrangements are subjected to. In the present study we evaluated (1) the possibility to improve locomotor recovery after complete transection of the spinal cord by means of an adeno-associated (AAV) viral vector expressing the neurotrophin brain-derived neurotrophic factor (BDNF) in lumbar spinal neurons caudal to the lesion site and (2) how the spinal cord transection and BDNF treatment affected neurotransmission in the segments caudal to the lesion site. BDNF overexpression resulted in clear increases in expression levels of molecules involved in glutamatergic (VGluT2) and GABAergic (GABA, GAD65, GAD67) neurotransmission in parallel with a reduction of the potassium-chloride co-transporter (KCC2) which contributes to an inhibitory neurotransmission. BDNF treated animals showed significant improvements in assisted locomotor performance, and performed locomotor movements with body weight support and plantar foot placement on a moving treadmill. These positive effects of BDNF local overexpression were detectable as early as two weeks after spinal cord transection and viral vector application and lasted for at least 7 weeks. Gradually increasing frequencies of clonic movements at the end of the experiment attenuated the quality of treadmill walking. These data indicate that BDNF has the potential to enhance the functionality of isolated lumbar circuits, but also that BDNF levels have to be tightly controlled to prevent hyperexcitability.
Highlights
Mechanisms underlying the improvement of motor abilities after spinal cord injury are still a matter of debate; brain-derived neurotrophic factor (BDNF) is considered an important player [1–3]
Depolarizing action in our experimental system. This is the first study correlating the effect of quantified overexpression of BDNF in spinalized rats with segmental changes in excitatory and inhibitory amino acid neurotransmitters, expression of neurotransmitter-related molecules
BDNF expression translated into robust early improvements in locomotor abilities, suggesting that in principle a stimulation of excitatory circuits in spinal pattern generators could be of clinical relevance
Summary
Mechanisms underlying the improvement of motor abilities after spinal cord injury are still a matter of debate; brain-derived neurotrophic factor (BDNF) is considered an important player [1–3]. After a complete spinal cord transection, this adaptation involves functional reorganization as demonstrated at the behavioral, biochemical, structural, and electrophysiological levels [5,6,7,8,9,10]. Cellular electrophysiological parameters are changed after BDNF delivery or training, increasing motoneuron susceptibility to discharge [8,35,36] and activating lumbar interneurons implicated in improved stepping functions [36]. These changes are most likely related to the contribution of BDNF to regulation of the neuronspecific potassium-chloride co-transporter (KCC2) [24,36,37,38]
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