Rehabilitative Training Interacts with Ischemia-Instigated Spine Dynamics to Promote a Lasting Population of New Synapses in Peri-Infarct Motor Cortex

Abstract

After subtotal infarcts of primary motor cortex (M1), motor rehabilitative training (RT) promotes improvements in paretic forelimb function that have been linked with its promotion of structural and functional reorganization of peri-infarct cortex, but how the reorganization unfolds is scantly understood. Cortical infarcts also instigate a prolonged period of dendritic spine turnover in peri-infarct cortex. Here we investigated the possibility that synaptic structural responses to RT in peri-infarct cortex reflect, in part, interactions with ischemia-instigated spine turnover. This was tested after artery-targeted photothrombotic M1 infarcts or Sham procedures in adult (4 months) C57BL/6 male and female GFP-M line (n = 24) and male yellow fluorescent protein-H line (n = 5) mice undergoing RT in skilled reaching or no-training control procedures. Regardless of training condition, spine turnover was increased out to 5 weeks postinfarct relative to Sham, as was the persistence of new spines formed within a week postinfarct. However, compared with no-training controls, new spines formed during postinfarct weeks 2-4 in mice undergoing RT persisted in much greater proportions to later time points, by a magnitude that predicted behavioral improvements in the RT group. These results indicate that RT interacts with ischemia-instigated spine turnover to promote preferential stabilization of newly formed spines, which is likely to yield a new population of mature synapses in peri-infarct cortex that could contribute to cortical functional reorganization and behavioral improvement. The findings newly implicate ischemia-instigated spine turnover as a mediator of cortical synaptic structural responses to RT and newly establish the experience dependency of new spine fates in the postischemic turnover context.SIGNIFICANCE STATEMENT Motor rehabilitation, the main treatment for motor impairments after stroke, is far from sufficient to normalize function. A better understanding of neural substrates of rehabilitation-induced behavioral improvements could be useful for understanding how to optimize it. Here, we investigated the nature and time course of synaptic responses to motor rehabilitative training in vivo Focal ischemia instigated a period of synapse turnover in peri-infarct motor cortex of mice. Rehabilitative training increased the stability of new synapses formed during the initial weeks after the infarct, the magnitude of which was correlated with improvements in skilled motor performance. Therefore, the maintenance of new synapses formed after ischemia could represent a structural mechanism of rehabilitative training efficacy.