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

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 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.

WITHDRAWN: Identification of Non-coding RNA Biomarkers in Stress-induced Depression via Comprehensive Analysis of Competing Endogenous RNA Network

“…It was reported that the NLRP3 in ammasome modulated MAPK signaling pathway in depressive mice [40]. In conclusion, we are consistent with the previous study that protein phosphorylation and MAPK signaling pathway were known to potential depression-related pathogenesis [41,42].…”

Antidepressant mechanism of classical herbal formula lily bulb and Rehmannia decoction: insights from gene expression profile of medial prefrontal cortex of mice with stress‐induced depression‐like behavior

“…Our data showed that these DEGs were mainly enriched in the neurotrophin signaling pathway, insulin signaling pathway, alcoholism, GABAergic synapse, glutamatergic synapse, amphetamine addiction, MAPK signaling pathway, PI3K‐Akt signaling pathway and circadian rhythm (Table ). Interestingly, these signaling pathways are involved in the pathophysiology and treatment of depression . For example, GABA and glutamate neurotransmitter deficits are used to explain the neurobiological abnormalities associated with MDD, which has been well‐accepted .…”

Involvement of p38 MAPK in Synaptic Function and Dysfunction

“…In addition, it has been shown that a specific genetic ablation of the p38α isoform virtually abolishes NMDA-dependent LTD when targeting astrocytes, while producing no effect or slightly enhancing LTD when targeting neurons. These data indicate that astrocytic p38α is involved in activity-dependent glutamate release from astrocytes, contributing to astrocyte-to-neuron communication [39]. The authors concluded that the activity of p38α MAPK in the astrocyte contributes to hippocampal NMDA-dependent LTD, and is capable of modulating long-term memory in vivo [39].…”