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.
Highlights
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
We first investigated whether conventional LTD induced by low-frequency stimulation (LFS; 1 Hz, 300 pulses) of Schaffer collaterals (SCs) triggers astrocytic activity
Expression was directed to astrocytes by in vivo injections of adeno-associated viruses (AAV2/5) bearing the GFAP promoter (Fig. 1a, b)
Summary
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. In the case of Nmethyl-D-aspartate receptor (NMDAR)-dependent LTD, even though the molecular details are still being elucidated, it is well accepted that the core mechanism relies exclusively on neuronal events: (i) prolonged, low-frequency release of glutamate from the presynaptic terminal, (ii) activation of postsynaptic NMDARs, (iii) engagement of specific signaling cascades at the postsynaptic terminal, and (iv) endocytic removal of α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors (AMPARs) from the postsynaptic membrane[3]. We show that astrocytes are core elements of the LTD mechanism by providing the glutamate transmitter responsible for postsynaptic depression of CA3–CA1 synaptic transmission This mechanism requires Ca2+ signaling and SNARE-dependent exocytosis in the astrocyte. We show that the activity of p38α mitogen-activated protein kinase (MAPK) in the astrocyte (and not in the neuron) is required for hippocampal LTD, and modulates long-term memory in vivo
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