The coordinated plasticity of astrocytes and synapses in learning and post-stroke recovery

Abstract

Stroke typically occurs in one hemisphere and often results in long-term disability in the contralateral body side (paretic side). Greater reliance on the non-paretic body side is used to compensate for this disability. Meanwhile, the brain undergoes degenerative and plastic changes in both hemispheres. Many previous studies have investigated post-stroke brain plasticity, and explored how it is shaped by behavioral experiences, to better understand the mechanisms of functional recovery. However, these studies have primarily focused on neurons and synapses. Given the abundant evidence that astrocytes actively control activity and plasticity of synapses, it seems reasonable to investigate how astrocytes are involved in behavior- and injury-driven brain plasticity. The central hypothesis of these studies is that synaptic plasticity underlying motor skill learning and post-stroke motor rehabilitation is coordinated with structural and functional plasticity of perisynaptic astrocytes. This was tested in a rat model of motor learning and "re-learning" after unilateral stroke-like damage to sensorimotor cortex. In the contralesional homotopic cortex, astrocytic volume varied with lesion size, as did the number of synapses. In the remaining motor cortex of the injured hemisphere, rehabilitative training with the paretic limb increased the proportion of astrocytic membrane apposed with synapses along with density of synapses. Furthermore, the percentage of synapses with astrocytic contacts was significantly correlated with functional outcome. Training with the non-paretic limb also induced greater synaptic density than controls in peri-infarct cortex, but functional outcome was negatively correlated with this and was not correlated with astrocytic contacts with synapses. These findings suggest that plasticity of, and association between, synapses and astrocytes vary with the type of experiences. Moreover, pharmacological upregulation of astrocytic glutamate uptake, which is one of the key ways that astrocytes modulate synaptic activity, interfered with functional recovery, supporting a critical role for astrocytic glutamate uptake in functional outcome following a stroke. Taken together, these studies contribute to better understanding of how lesions and experiences affect plasticity of astrocytes and synapses. These findings suggest that post-injury experiences alter astrocytic association with synapses, and that the coordinated plasticity of astrocytes and synapses is likely to be a critical mediator to functional outcome.