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Glial ATP and Large Pore Channels Modulate Synaptic Strength in Response to Chronic Inactivity

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Abstract

A key feature of neurotransmission is its ability to adapt to changes in neuronal environment, which is essential for many brain functions. Homeostatic synaptic plasticity (HSP) emerges as a compensatory mechanism used by neurons to adjust their excitability in response to changes in synaptic activity. Recently, glial cells emerged as modulators for neurotransmission by releasing gliotransmitters into the synaptic cleft through pathways that include P2X7 receptors (P2X7R), connexons, and pannexons. However, the role of gliotransmission in the activity-dependent adjustment of presynaptic strength is still an open question. Here, we investigated whether glial cells participate in HSP upon chronic inactivity and the role of adenosine triphosphate (ATP), connexin43 hemichannels (Cx43HCs), and pannexin1 (Panx1) channels in this process. We used immunocytochemistry against vesicular glutamate transporter 1 (vGlut1) to estimate changes in synaptic strength in hippocampal dissociated cultures. Pharmacological manipulations indicate that glial-derived ATP and P2X7R are required for HSP. In addition, inhibition of Cx43 and Panx1 channels reveals a pivotal role for these channels in the compensatory adjustment of synaptic strength, emerging as new pathways for ATP release upon inactivity. The involvement of Panx1 channels was confirmed by using Panx1-deficient animals. Lacking Panx1 in neurons is sufficient to prevent the P2X7R-dependent upregulation of presynaptic strength; however, the P2X7R-dependent compensatory adjustment of synapse density requires both neuronal and glial Panx1. Together, our data supports an essential role for glial ATP signaling and Cx43HCs and Panx1 channels in the homeostatic adjustment of synaptic strength in hippocampal cultures upon chronic inactivity.

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Funding

The present study was supported by grants to N.V. and V.A. by the Comisión Sectorial de Investigación Científica (CSIC-UdelaR) and by the Program for the Development of Basic Sciences (PEDECIBA). A.R. and A.C received a Master Fellowship from the Agencia Nacional de Investigación e Innovación (ANII) and CSIC, UdelaR, respectively.

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  1. Alberto Rafael and Andrea Cairus contributed equally to this work.

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  1. Departamento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

    Alberto Rafael, Andrea Cairus, Marina Tizzoni, Verónica Abudara & Nathalia Vitureira

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Rafael, A., Cairus, A., Tizzoni, M. et al. Glial ATP and Large Pore Channels Modulate Synaptic Strength in Response to Chronic Inactivity. Mol Neurobiol 57, 2856–2869 (2020). https://doi.org/10.1007/s12035-020-01919-0

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