Cortical hyperactivity beyond immune attack : pivotal role of TNF-alpha in early Multiple Sclerosis
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Abstract
The central nervous system (CNS) is the primary target in both multiple sclerosis (MS) and the animal model of experimental autoimmune encephalomyelitis (EAE). The disease is mainly driven by infiltrating myelin specific T cells that are peripherally activated by antigen presenting cells (APCs), yet little known about how the disease itself affects neuronal activity patterns in the different cortices in vivo. In the last decades, growing advancement in functional imaging has been successfully applied in several other CNS diseases but its real-time application in CNS autoimmunity has not been achieved. Here, we employed in vivo two-photon Ca2+ imaging to study the activity patterns of neurons in the visual cortex of mice with different phases of the EAE. By using this method, we identified spontaneous activity of the network in the visual cortex that had drastically increased followed by increased hyperactive cells in remission (disease phase with no or mild symptoms present) rather than in relapse where the disease symptoms were less prominent. In addition, frontal cortex also displayed similar activity pattern supporting that it is a cortex-wide phenomenon and such alteration of activity is independent of demyelination or cellular infiltration. Furthermore, cortical TNF-α level had significantly elevated throughout the cortex in remission mice and a reversal of increased cortex activity was achieved by intraventricular injections of infliximab, a monoclonal antibody specific against TNF-α. CamKII+ excitatory neurons were found to be surrounded by soluble TNF-α. Taken together, this thesis furnishes advances of two-photon microscopy to enable functional studies of visual and frontal cortices neuronal activity in vivo in different disease states of EAE.