400 - Intensive rehabilitative protocol restores gait disfunction caused by experimental Cerebral Palsy in rats – modulation of cortical hyperexcitability as a mechanism of neuroprotection

Poster Number: 400
Publication Number: 400.236

Eduardo F. Sanches, University of Geneva, Geneva, Geneve, Switzerland; Dini Ho, University of Geneva, Geneva, Geneve, Switzerland; Yohan van de Looij, University of Geneva, Geneva, Geneve, Switzerland; Audrey Toulotte, UNIGE, Geneva, Geneve, Switzerland; Charlotte Dennez, Tours University, Lausanne, Vaud, Switzerland; Jérôme Mairesse, UNIGE, Genève, Geneve, Switzerland; Laetitia Baud, EPFL, Geneva, Geneve, Switzerland; Quentin Barraud, EPFL, Geneva, Geneve, Switzerland; Olivier Baud, Hôpitaux Univ Genève, Geneva, Geneve, Switzerland; Grégoire Courtine, EPFL, Geneva, Geneve, Switzerland; Stéphane Sizonenko, Univedity of Geneva, Geneva, Geneve, Switzerland

Background: Cerebral Palsy (CP) is a major cause of motor and cognitive disability in children due to injury to the developing brain. Risk factors include preterm birth, asphyxia, fetoplacental infection and/or inflammation leading to neurological disorders. Experimental CP has been shown to cause cortical damage, hypomyelination and functional impairments. HABIT-ILE (Hand and Arm Bimanual Intensive Training Including Lower Extremity) is a 2-week intensive rehab protocol based in sensorimotor training  and has proven to decrease motor impairments and to induce plastic changes in white matter tract following CP, however, the molecular substrates for the recovery are not known

Objective: Using a CP rat model, we tested the protective role of a HABIT-ILE like strategy using the combination (EETT) of treadmill training (TT) and environmental enrichment (EE) and assessed brain and behavioral function, macro and microstructural damage and the expression of proteins potentially involved in the neuroprotection

Design/Methods: Pregnant Wistar rats were injected with LPS (200mg/kg ip on E18 and E19). At P0, pups were exposed to anoxia for 20’ in a chamber at (37°C). From postnatal day 2 to 21, animals' hindlimbs movements were restricted for 16h/day during the dark cycle. HABIT-ILE like rehab (EETT), TT and EE lasted from P21 to P28. TT - 15 min/day at 7cm/s. EE - 7 days in enriched cages with multiple sensorimotor stimulus. 3D kinematic gait analysis was performed at P21 and P28. Rota-Rod (RR)  and brain Functional Ultrasound (FUS) were performed at P28. Brain tissue was collected for ex-vivo MRI, histological analysis and protein expression

Results: CP group had worse performance in RR and impaired gait pattern. EETT rescued partially motor performance in RR and reversed abnormalities in the gait caused by CP. Ex-vivo DTI/NODDI showed loss of brain microstructure in CP rats, not reversed by EETT. FUS revealed that CP rats had hyperconnectivity among brain regions reversed by EETT.  CPETT group had preservation of myelination in the corpus callosum and decreased astrogliosis in cortex and hippocampus. Moreover, EETT showed robust effects modulating BDNF signaling, interfering in inflammatory processes and decreasing cortical excitatory dysfunction (increased PSD95, Synaptophysin and vGut1) induced by CP Conclusion(s): Translational HABIT-ILE (EETT) reversed hind limbs dysfunction and promoted tissue rescue following experimental CP through multiple molecular mechanisms and support the concept that early (and intense) protocols of physical rehabilitation induce neuroprotective effects following injuries to the developing CNS