The role of astrocytes in Multiple Sclerosis synaptopathy

Multiple Sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system. Synaptopathy, characterized, in part, by an imbalance between excitatory and inhibitory neurotransmission, has emerged as an important component of MS pathophysiology and may lead to neuronal hyperexcitability. Astrocytes are key regulators of synaptic function; however, their role in synaptic alterations associated with MS remains poorly understood. Thus, this study investigated the role of astrocytes in MS-associated synaptopathy. Male Swiss mice were fed either a control diet or a diet containing cuprizone (CPZ) (0.2%) for 5 weeks to induce demyelination. Procedures were approved by the Ethics Committee on Animal Care (CEUA-UENF) under protocol No.542. Visual cortex samples were processed by immunofluorescence to evaluate astrocytic and synaptic markers. Astrocytic reactivity was assessed by Glial Fibrillary Acidic Protein (GFAP), predominantly expressed in astrocytes; glutamate homeostasis was evaluated through the astrocytic excitatory amino acid transporters 1 and 2 (GLAST and GLT-1); and glutamate metabolism was assessed through glutamine synthetase (GS). The inhibitory system was evaluated by parvalbumin expression, a marker of GABAergic interneurons, while perineuronal nets were evaluated by Wisteria floribunda agglutinin (WFA) levels. CPZ-treated animals showed increased GFAP expression, consistent with the occurrence of astrogliosis, along with increased expression of GLT-1 and GLAST and elevated GS levels, suggesting alterations in glutamate homeostasis and metabolism. An increase in parvalbumin and WFA expression was also observed, suggesting a possible compensatory response of the inhibitory system in response to alterations in neurotransmission.These findings indicate that astrocytic alterations associated with demyelination may contribute to MS-associated synaptopathy and provide new insights into the mechanisms underlying neuronal hyperexcitability.