title: Vector-induced NT-3 expression in rats promotes collateral growth of injured corticospinal tract axons far rostral to a spinal cord injury.
abstract: Rewiring the injured corticospinal tract (CST) by promoting connections between CST axons and spared neurons is a strategy being explored experimentally to achieve improved recovery of motor function after spinal cord injury (SCI). Reliable interventions to promote and direct growth of collaterals from injured CST axons are in high demand to promote functionally relevant detour pathways. A promising tool is neurotrophin-3 (NT-3), which has shown growth-stimulating and chemo-attractive effects for spared CST axons caudal to a CST lesion. Yet, efforts to promote growth of injured CST axons rostral to a SCI with NT-3 have been less successful to date. Evidence indicates that immune activation in the local growth environment, either intrinsic or induced by the endotoxin lipopolysaccharide (LPS), can play a decisive role in the CST's responsiveness to NT-3. Here, we test the potential of NT-3 as a tool to enhance and direct collateral growth from the injured CST rostral to a SCI (1) using long-term expression of NT-3 by adeno-associated viral vectors, (2) with and without stimulating the immune system with LPS. Our results indicate that inducing a growth response from injured CST axons into a region of vector-mediated NT-3 expression is possible in the environment of the spinal cord rostral to a SCI, but seems dependent on the distance between the responding axon and the source of NT-3. Our findings also suggest that injured CST axons do not increase their growth response to NT-3 after immune activation with LPS in this environment. In conclusion, this is to our knowledge the first demonstration that NT-3 can be effective at promoting growth of injured CST collaterals far rostral to a SCI. Making NT-3 available in close proximity to CST target axons may be the key to success when using NT-3 to rewire the injured CST in future investigations.
authors.affiliation: Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, MSB 453, Canada. Electronic address: nweishau@uwo.ca.
authors.forename: N
authors.initials: N
authors.lastname: Weishaupt
authors.affiliation: Department of Rehabilitation Medicine, University of Alberta, 3-88 Corbett Hall, Edmonton, AB T6E 2G4, Canada. Electronic address: almason@ualberta.ca.
authors.forename: A L O
authors.initials: AL
authors.lastname: Mason
authors.affiliation: Department of Rehabilitation Medicine, University of Alberta, 3-88 Corbett Hall, Edmonton, AB T6E 2G4, Canada. Electronic address: clhurd@ualberta.ca.
authors.forename: C
authors.initials: C
authors.lastname: Hurd
authors.affiliation: Centre for Neuroscience, University of Alberta, 3-88 Corbett Hall, Edmonton, AB T6E 2G4, Canada. Electronic address: zacnicte@ualberta.ca.
authors.forename: Z
authors.initials: Z
authors.lastname: May
authors.affiliation: Department of Rehabilitation Medicine, University of Alberta, 3-88 Corbett Hall, Edmonton, AB T6E 2G4, Canada. Electronic address: zmyslowskid@mymail.macewan.ca.
authors.forename: D C
authors.initials: DC
authors.lastname: Zmyslowski
authors.affiliation: Centre for Neuroscience, University of Alberta, 3-88 Corbett Hall, Edmonton, AB T6E 2G4, Canada; Department of Pharmacology, University of Alberta, 9-21 Medical Sciences, Edmonton, AB T6G 2H7, Canada. Electronic address: dgalleguillos@ualberta.ca.
authors.forename: D
authors.initials: D
authors.lastname: Galleguillos
authors.affiliation: Centre for Neuroscience, University of Alberta, 3-88 Corbett Hall, Edmonton, AB T6E 2G4, Canada; Department of Pharmacology, University of Alberta, 9-21 Medical Sciences, Edmonton, AB T6G 2H7, Canada. Electronic address: ssipione@ualberta.ca.
authors.forename: S
authors.initials: S
authors.lastname: Sipione
authors.affiliation: Centre for Neuroscience, University of Alberta, 3-88 Corbett Hall, Edmonton, AB T6E 2G4, Canada; Faculty of Rehabilitation Medicine, University of Alberta, 3-87 Corbett Hall, Edmonton, AB T6G 2G4, Canada. Electronic address: karim.fouad@ualberta.ca.
authors.forename: K
authors.initials: K
authors.lastname: Fouad
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D005260:Female; D009416:Nerve Regeneration / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism*; D011712:Pyramidal Tracts / Q000378:metabolism* / Q000503:physiopathology; D011917:Rats, Inbred Lew; D020127:Recovery of Function / Q000187:drug effects; D013116:Spinal Cord / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D020933:Neurotrophin 3
keywords: axonal growth; lipopolysaccharide; neurotrophic factor; plasticity; viral vector