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Astroglial TNFR2 modulation of hippocampal synaptic function in the EAE model of multiple sclerosis
Location: 87
Mentor: Dr. Roberta Brambilla
Multiple Sclerosis (MS) is a chronic neurodegenerative disease that leads to sensory-motor dysfunction and cognitive impairments, affecting approximately 2.8 million individuals worldwide. Cognitive dysfunction in MS has been linked to impaired synaptic function and plasticity, a process requiring the bidirectional communication between astrocytes and neurons. An important regulator of synaptic plasticity is tumor necrosis factor (TNF), which signals through two receptors, TNFR1 and TNFR2, both expressed in astrocytes. While TNFR1 is needed for proper physiologic synaptic activity, it becomes overactivated in the experimental autoimmune encephalomyelitis (EAE) model of MS, impairing synaptic function and cognition. However, the role of TNFR2 in these processes remains poorly understood. Preliminary research in the Brambilla lab shows that ablation of astroglial TNFR2 leads to hippocampal gliosis and dendritic spine damage at prodromic EAE. These early changes precede cognitive impairments seen at chronic EAE. In this study we aimed to quantify the expression of key hippocampal synaptic proteins and glutamate receptors throughout EAE upon ablation of astroglial TNFR2. Our findings indicate that TNFR2 ablation in astrocytes alters the expression of these proteins throughout EAE, with the majority being upregulated at prodomic EAE. These alterations may lead to the dendritic spine damage and cognitive deficits we observed previously. Together, these findings indicate that astroglial TNFR2 signaling has a protective role in containing/counteracting synaptic and cognitive dysfunction associated with EAE and MS. Ongoing experiments aim to explore whether overexpression of astroglial TNFR2 can rescue these deficits seen with ablation of TNFR2. Ultimately our goal is to explore the potential of TNFR2 as a therapeutic target for counteracting cognitive dysfunction in MS.
