Transgene-mediated GDNF expression enhances synaptic connectivity and GABA transmission to improve functional outcome after spinal cord contusion.

Journal of Neurochemistry
Angela KoelschMarina Mata

Abstract

Glial cell line-derived trophic factor (GDNF) is a peptide with pleiotropic survival and growth-promoting effects on neurons. We found that intraspinal injection of a non-replicating herpes simplex virus-based vector coding for GDNF 2 h after blunt trauma to the thoraco-lumbar spinal cord produced sustained improvement in motor behavioral outcomes up to 5 weeks following injury. The improvement in behavior correlated with an increase in synaptophysin and glutamic acid decarboxylase (GAD) in the spinal cord at the level of injury. Addition of recombinant GDNF protein to primary spinal cord neurons in-vitro resulted in enhanced neurite growth and a marked increase in protein levels of GAD65 and GAD67, synapsin I and synaptophysin. GDNF-mediated increases in GAD and the synaptic markers were blocked by the MEK inhibitor UO126, but not by the phosphoinositide 3-kinase inhibitor LY294002. These results suggest that GDNF, acting through the MEK-ERK pathway enhances axonal sprouting, synaptic connectivity, and GABAergic neurotransmission in the spinal cord, that result in improved behavioral outcomes after spinal cord contusion injury.

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Citations

Jan 25, 2013·Acta Neuropathologica·Min-Chi KuHelmut Kettenmann
Jul 8, 2014·Therapeutic Delivery·Kenzo UchidaHisatoshi Baba
Dec 19, 2013·Frontiers in Biology·Chandler L WalkerXiao-Ming Xu
Jun 7, 2011·Pharmacology & Therapeutics·Chihiro Tohda, Tomoharu Kuboyama
Mar 16, 2017·Journal of Tissue Engineering and Regenerative Medicine·Bingkun K ChenAnthony J Windebank
Aug 11, 2017·Journal of Neurotrauma·Konstantin RosichAmgad Hanna
Aug 28, 2016·Translational Stroke Research·Naohiro EgawaKen Arai
Jul 31, 2020·Molecular Therapy. Methods & Clinical Development·Daewook KimSujeong Kim

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