Astrocyte and neuron cooperation in long-term depression

Abstract

Activity-dependent long-term changes in synaptic transmission known as synaptic plasticity are fundamental processes in brain function and are recognized as the cellular basis of learning and memory. While the neuronal mechanisms underlying synaptic plasticity have been largely identified, the involvement of astrocytes in these processes has been less recognized. However, astrocytes are emerging as important cells that regulate synaptic function by interacting with neurons at tripartite synapses. In this review, we discuss recent evidence suggesting that astrocytes are necessary elements in long-term synaptic depression (LTD). We highlight the mechanistic heterogeneity of astrocyte contribution to this form of synaptic plasticity and propose that astrocytes are integral participants in LTD.

Keywords: calcium signaling; gliotransmission; long-term depression; synaptic plasticity; tripartite synapses.

Figure 1.. Comparison of neuronal versus tripartite synapse mechanisms mediating LTD.

Schematic figure summarizing the variety of classical LTD (A) and revised LTD (B) models taking into account astrocytic signaling. LTD can be expressed as changes in both pre- or postsynaptic elements and may depend on activation of the different receptors noted in the figure in green: N-methyl-D-aspartate receptors (NMDARs), metabotropic glutamate receptors (mGluRs), type 1 adenosine receptors (A1Rs), or endocannabinoid receptors (CB1Rs). The revised LTD model (B), which incorporates astrocyte participation, was investigated using different approaches: blocking calcium activity of astrocytes using BAPTA in astrocytes or IP₃R2 knock-out mice, blocking exocytosis by SNARE proteins, or p38α MAPK removal. See main text and Table 1 for additional details and references.

Figure 2.. Various mechanisms of astrocyte involvement in different forms of LTD.

Different astrocytic neurotransmitter receptors and transporters, intracellular signaling pathways and gliotransmitters have been demonstrated to be necessary for various forms of LTD. Activation of neurotransmitter receptors, such as type 1 endocannabinoid receptors (CB1Rs) or metabotropic glutamate receptors (mGluRs), in astrocytes triggers intracellular signaling mechanisms, including IP₃R2-mediated calcium elevations and p38α mitogen-activated protein kinase (p38α MAPK) activation. The astrocytic calcium signal stimulates SNARE-protein dependent vesicular release of gliotransmitters, such as glutamate, ATP/adenosine and D-serine. These gliotransmitters act on neuronal receptors, such as mGluRs, adenosine (A1R), purinergic (P2YR) and N-Methyl-D-aspartate (NMDAR) receptors, contributing to the synaptic signaling involved in LTD.

Figure 3.. Comparison of classical and revised views of different forms of LTD.

(A)Left, Classical view of NMDAR-LTD, whereby presynaptic glutamate (1) activates postsynaptic NMDARs (2), triggering depolarization and influx of calcium (3) and AMPAR internalization (4). Right, Updated mechanism involving astrocytes, whereby presynaptic glutamate also activates astrocytes (2) and triggers the release of astrocytic glutamate that activates postsynaptic NDMARs (3), leading to depolarization and influx of calcium and AMPAR internalization (4). (B)Left, Classical view of CB1R-LTD, whereby postsynaptic depolarization and calcium influx (1) trigger the release of endocannabinoids (2) that bind presynaptic CB1Rs (3), resulting in decreased glutamate release (4). Right, Updated mechanism involving astrocytes, whereby endocannabinoids (1) also activate astrocyte CB1Rs (2), generating a calcium increase and stimulating the release of glutamate (3), which activates postsynaptic NMDA receptors (4) to increase AMPAR internalization (5). (C)Left, Classical view of a form of neocortical spike timing-dependent LTD (t-LTD), whereby the coincidence of postsynaptic mGluR activation during synaptic activity (1) and calcium influx evoked by back-propagating action potentials (2) triggers the release of endocannabinoids that bind presynaptic CB1Rs (3), resulting in decreased glutamate release (4). Right, Updated mechanism involving astrocytes, whereby endocannabinoids released during t-LTD induction (1) activate CB1Rs on astrocytes (2), which induces glutamate/D-Serine release in a calcium-dependent manner (3) that activate presynaptic NMDAR (4) together with glutamate released from presynaptic neurons to induce t-LTD (5). (D)Left, Classical view of mGluR-LTD, whereby presynaptic glutamate release (1) activates mGluRs (2), triggering a calcium increase (3) and AMPAR internalization (4). Right, Updated view involving astrocytes, whereby presynaptic glutamate also activates astrocytes (2) and triggers the release of astrocytic glutamate that activates postsynaptic mGluRs (3), leading to depolarization and influx of calcium (4), and AMPAR internalization (5).