Authors: S. F. IRVINE, S. GIGOUT, P. M. WARREN, J. C. F. KWOK
To promote recovery after spinal cord injury (SCI), treatments aim to enhance regeneration of severed axons and the plasticity of surviving circuitry. Enzymatic removal of perineuronal nets (PNNs), a plasticity brake in the adult central nervous system (CNS), using intrathecal chondroitinase ABC (ChABC) injections successfully enhances plasticity and functional recovery, particularly in SCI models. PNNs envelop neuronal sub-populations throughout the CNS providing stabilisation of circuitry and thus regulation of plasticity. Whilst ChABC has proven beneficial to recovery alongside other treatments including rehabilitation, there are significant hurdles in regards to clinical application. This study aims to investigate an alternative method of PNN removal via non-invasive systemic PNN inhibition (PNNi) in combination with rehabilitation and its efficacy to enhance motor recovery after acute SCI. Firstly, as much of the PNN-associated neuronal populations are still relatively unknown in the spinal cord, we characterised normal PNN expression in the ventral motor pools using immunohistochemistry alongside specific motoneurone (Mn) markers. Compared to the acclaimed universal PNN marker Wisteria floribunda agglutinin lectin, the major PNN component aggrecan denoted significantly more PNNs around Mns. Selective Mn labelling revealed that PNNs encircled ~90% of alpha Mns, likely reflecting the population involved in the above mentioned motor recovery after SCI. To test the therapeutic efficacy of PNNi, adult female Lister Hooded rats received a moderate contusion to the T9 spinal cord and were assigned to treatment groups receiving PNNi or vehicle, with or without combination of rehabilitative treadmill training. Recovery was assessed using behavioural tests such as open field test hindlimb tests (BBB), horizontal ladder and von Frey assay. Preliminary results suggest that the systemic PNNi predominantly removes PNNs from the spinal cord, rather than the brain. Hindlimb motor functions were improved following rehabilitation. However, systemic plasticity enhancement seems to affect the forelimb function. Current experiments focus on defining the therapeutic window for optimal plasticity. Our data suggests that chronic PNNi application may provide a non-invasive strategy to enhance plasticity and regeneration after SCI.
*S. F. IRVINE1, S. GIGOUT1, P. M. WARREN1,2, J. C. F. KWOK1,3;
1Sch. of Biomed. Sciences, Fac. of Biol. Sci., Univ. of Leeds, Leeds, United Kingdom; 2Wolfston Ctr. for Age Related Dis., Kings Col. London, London, United Kingdom; 3Ctr. of Reconstructive Neurosciences, Inst. of Exptl. Med., The Czech Acad. of 7 Sci., Prague, Czech Republic. Enhancement of plasticity for functional recovery after spinal cord injury. Program No. 298.03. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.