In Vivo Assessment of Cortical Astrocyte Network Dysfunction During Autoimmune Demyelination: Correlation With Disease Severity

Abstract

Cortical damage and dysfunction is a pathological hallmark of multiple sclerosis (MS) that correlates with the severity of physical and cognitive disability. Astrocytes participate in MS pathobiology through a variety of mechanisms, and abnormal astrocytic calcium signaling has been pointed as a pathogenic mechanism of cortical dysfunction in MS. However, in vivo evidence supporting deregulation of astrocyte calcium-dependent mechanisms in cortical MS is still limited. Here, we applied fiber photometry to the longitudinal analysis of spontaneous and sensory-evoked astrocyte network activity in the somatosensory cortex of mice in an experimental autoimmune encephalomyelitis (EAE). We found that freely moving EAE mice exhibit spontaneously occurring astrocyte calcium signals of increased duration and reduced amplitude. Concomitantly, cortical astrocytes in EAE mice responded to sensory stimulation with calcium events of decreased amplitude. The emergence of aberrant astrocyte calcium signals in the somatosensory cortex paralleled the onset of neurological symptomatology, and changes in the amplitude of both spontaneous and evoked responses were selectively correlated to the severity of neurological deficits. These results highlight the imbalance of astrocyte network activity in the brain cortex during autoimmune inflammation and further support the relevance of astrocyte-based pathobiology as an underlying mechanism of cortical dysfunction in MS.