Autoimmune inflammation triggers aberrant astrocytic calcium signaling to impair synaptic plasticity

Baraibar, A. M.; Colomer, T.; Moreno-Garcia, A.; Bernal-Chico, A.; Sanchez, E.; Utrilla, C.; Serrat, R.; Soria-Gomez, E.; Rodriguez-Antiguedad, A.; Araque, A.; Matute, C.; Marsicano, G.; Mato, S.

doi:10.1101/2023.08.01.551248

bioRxiv · 10.1101/2023.08.01.551248

Autoimmune inflammation triggers aberrant astrocytic calcium signaling to impair synaptic plasticity

Baraibar, A. M.·Colomer, T.·Moreno-Garcia, A.·Bernal-Chico, A.·Sanchez, E.·Utrilla, C.·Serrat, R.·Soria-Gomez, E.·Rodriguez-Antiguedad, A.·Araque, A.·Matute, C.·Marsicano, G.·Mato, S.

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Abstract

Cortical pathology involving inflammatory and neurodegenerative mechanisms is a hallmark of multiple sclerosis (MS) and a correlate of disease progression and cognitive decline. Astrocytes play a pivotal role in MS initiation and progression but astrocyte-neuronal network alterations contributing to gray matter pathology remain undefined. Here we measured astrocytic calcium in the experimental autoimmune encephalomyelitis (EAE) model of MS using fiber photometry in freely behaving mice and two-photon imaging ex vivo. We identified the emergence of spontaneously hyperactive cortical astrocytes displaying calcium transients of increased duration as well as dysfunctional responses to cannabinoid, glutamate and purinoreceptor agonists during acute EAE disease. Deficits in astrocyte calcium responses are associated to abnormal signaling by Gi and Gq protein coupled receptors in the inflamed cortex and are partially mirrored in cells activated with pro-inflammatory factors both in vitro and ex vivo thus suggesting cell-autonomous effects of the cortical neuroinflammatory environment. Finally, we show that deregulated astrocyte calcium activity is associated to an enhancement of glutamatergic gliotransmission and a shift of astrocyte-mediated short-term and long-term plasticity mechanisms towards synaptic potentiation. Overall our data identities astrocyte-neuronal network dysfunction as key pathological feature of the inflammatory gray matter that may contribute to MS symptomatology and clinical progression.

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Baraibar, A. M., Colomer, T., Moreno-Garcia, A., Bernal-Chico, A., Sanchez, E., Utrilla, C., Serrat, R., Soria-Gomez, E., Rodriguez-Antiguedad, A., Araque, A., Matute, C., Marsicano, G., Mato, S.. 2023-08-03. Autoimmune inflammation triggers aberrant astrocytic calcium signaling to impair synaptic plasticity. https://doi.org/10.1101/2023.08.01.551248

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