Astrocyte Glutamate Uptake and Water Homeostasis Are Dysregulated in the Hippocampus of Multiple Sclerosis Patients With Seizures

摘要

While seizure disorders are more prevalent among multiple sclerosis (MS) patients than the population overall and prognosticate earlier death & disability, their etiology remains unclear. Translational data indicate perturbed expression of astrocytic molecules contributing to homeostatic neuronal excitability, including water channels (AQP4) and synaptic glutamatetransporters (EAAT2), in a mouse model of MS with seizures (MStS). However, astrocytes in MStS have not been examined.To assess the translational relevance of astrocyte dysfunction observed in a mouse model of MStS, demyelinated lesionburden, astrogliosis, and astrocytic biomarkers (AQP4/EAAT2/ connexin-CX43) were evaluated by immunohistochemistry inpostmortem hippocampi from MS & MStS donors. Lesion burden was comparable in MS & MStS cohorts, but astrogliosiswas elevated in MStS CA1 with a concomitant decrease in EAAT2 signal intensity. AQP4 signal declined in MStS CA1 & CA3with a loss of perivascular AQP4 in CA1. CX43 expression was increased in CA3. Together, these data suggest that hippocampal astrocytes from MStS patients display regional differences in expression of molecules associated with glutamatebuffering and water homeostasis that could exacerbate neuronal hyperexcitability. Importantly, mislocalization of CA1perivascular AQP4 seen in MStS is analogous to epileptic hippocampi without a history of MS, suggesting convergentpathophysiology. Furthermore, as neuropathology was concentrated in MStS CA1, future study is warranted to determinethe pathophysiology driving regional differences in glial function in the context of seizures during demyelinating disease.