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

• Published in: Nature communications 2019-07, Vol.10 (1), p.2968-15, Article 2968
• Main Authors: Navarrete, Marta, Cuartero, María I., Palenzuela, Rocío, Draffin, Jonathan E., Konomi, Ainoa, Serra, Irene, Colié, Sandra, Castaño-Castaño, Sergio, Hasan, Mazahir T., Nebreda, Ángel R., Esteban, José A.
• Format: Article
• Language: English
• Subjects: 14; 14/35; 14/69; 45/41; 45/44; 631/378; 631/378/1595; 631/378/2591; 631/378/2596; 631/378/87; Animals; Astrocytes - enzymology; Behavior, Animal - physiology; Calcium ions; Calcium signalling; Clonal deletion; Cognitive ability; Communication; Conditioning, Psychological - physiology; Fear - physiology; Female; Gene deletion; Gene expression; Glutamic Acid - metabolism; Glutamic acid receptors (ionotropic); Hippocampus - cytology; Hippocampus - physiology; Humanities and Social Sciences; Kinases; Long term memory; Long-term depression; Long-Term Synaptic Depression - physiology; Male; MAP kinase; Memory; Memory, Long-Term - physiology; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 14 - metabolism; multidisciplinary; N-Methyl-D-aspartic acid receptors; Neurons; Neurons - physiology; Neurosciences; Optogenetics; Patch-Clamp Techniques; Plasticity; Receptors, N-Methyl-D-Aspartate - metabolism; Science; Science (multidisciplinary); SNAP receptors; Synapses; Synaptic plasticity; Synaptic Potentials - physiology; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10830-9

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 Ca 2+ 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. How astrocytes influence neuronal plasticity remains unclear, as they are typically considered as modulators of core mechanisms driven by neuronal components. Here, authors show that Long-term depression (LTD) induction in the hippocampus triggers calcium signaling in the astrocyte and enhances SNARE-dependent astrocytic glutamate release, which is then responsible for the activation of postsynaptic NMDA receptors and synaptic depression.