Astrocytic p38α MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory

Marta Navarrete (), María I. Cuartero, Rocío Palenzuela, Jonathan E. Draffin, Ainoa Konomi, Irene Serra, Sandra Colié, Sergio Castaño-Castaño, Mazahir T. Hasan, Ángel R. Nebreda and José A. Esteban ()
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Marta Navarrete: Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)
María I. Cuartero: Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)
Rocío Palenzuela: Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)
Jonathan E. Draffin: Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)
Ainoa Konomi: Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)
Irene Serra: Instituto Cajal (CSIC)
Sandra Colié: Barcelona Institute of Science and Technology
Sergio Castaño-Castaño: Achucarro Basque Center for Neuroscience
Mazahir T. Hasan: Achucarro Basque Center for Neuroscience
Ángel R. Nebreda: Barcelona Institute of Science and Technology
José A. Esteban: Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. The core mechanism for this form of plasticity is thought to be entirely neuronal. However, we now demonstrate that astrocytic activity drives LTD at CA3-CA1 synapses. We have found that LTD induction enhances astrocyte-to-neuron communication mediated by glutamate, and that Ca2+ signaling and SNARE-dependent vesicular release from the astrocyte are required for LTD expression. In addition, using optogenetic techniques, we show that low-frequency astrocytic activation, in the absence of presynaptic activity, is sufficient to induce postsynaptic AMPA receptor removal and LTD expression. Using cell-type-specific gene deletion, we show that astrocytic p38α MAPK is required for the increased astrocytic glutamate release and astrocyte-to-neuron communication during low-frequency stimulation. Accordingly, removal of astrocytic (but not neuronal) p38α abolishes LTD expression. Finally, this mechanism modulates long-term memory in vivo.

Date: 2019
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DOI: 10.1038/s41467-019-10830-9

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