Rémi Bos is a researcher in the P3M team at the institute of neurosciences of marseille (INT).
Seminar: Astrocyte-targeting therapy for reducing spasticity after spinal cord injury in mice.
Spasticity is a disabling motor deficit affecting ~75% of patients with spinal cord injury (SCI). Current therapeutic approaches give unsatisfactory results leaving SCI patients in severe pain and life discomfort. Thus, there is an urgent need to better understand the pathophysiological mechanisms underlying spasticity. Although most of the mechanisms proposed to explain spasticity focused on intrinsic neuronal elements, non-neuronal extrinsic cues have been overlooked so far. It is now well appreciated that astrocytes, a subtype of glial cells, are key players in controlling neuronal activity and homeostasis. In response to neuronal activity, astrocytes prevent neuronal hyper-excitability by buffering the extracellular K+ concentration increase mainly through the inwardly-rectifying K+ channel, Kir4.1 (a.k.a. Kcnj10). Here we identify the decrease of Kir4.1 function as triggering spastic-like symptoms in SCI mice. By combining two-photon calcium imaging with electrophysiology, immunohistochemistry, and genetic tools we report that SCI mice display reactive astrocytes surrounding lumbar motoneurons. Reactive astrocytes in spinal motor network are characterized by (i) changes in morphology, (ii) the presence of inflammatory markers, (iii) an altered intrinsic membrane properties, and (iv) the increase of intracellular Ca2+ signals. This latest results in pHi acidosis within astrocytes leading to the decrease of Kir4.1 function. By using a two-photon excited K+-sensitive fluorescent probe combined with electrophysiology, we noticed that SCI mice display an altered capacity of extracellular K+ uptake leading to motoneuron hyper-excitability. Finally, by using a targeted gene therapy in SCI mice, we overexpressed Kir4.1 in astrocytes leading to a significant decrease of in vivo spastic-like symptoms. This study provide an integrated comprehension of the astrocytic functions across scales (i.e from cellular to organismal) and broaden the spectrum of therapeutic targets for restoring compromised excitability in neurological diseases affecting Kir4.1 channels (epilepsy, Huntington, Rett Syndrome).
