Gliotransmitters travel in time and space

Abstract

The identification of the presence of active signaling between astrocytes and neurons in a process termed gliotransmission has caused a paradigm shift in our thinking about brain function. However, we are still in the early days of the conceptualization of how astrocytes influence synapses, neurons, networks, and ultimately behavior. In this Perspective, our goal is to identify emerging principles governing gliotransmission and consider the specific properties of this process that endow the astrocyte with unique functions in brain signal integration. We develop and present hypotheses aimed at reconciling confounding reports and define open questions to provide a conceptual framework for future studies. We propose that astrocytes mainly signal through high-affinity slowly desensitizing receptors to modulate neurons and perform integration in spatiotemporal domains complementary to those of neurons.

Figure 1. Bidirectional Neuron-astrocyte Communication Granted by High Affinity, Slowly Desensitizing Receptors

(A) Schematic drawing of the tripartite synapse illustrating the location of low and high affinity ligand receptors. (B) Neurotransmitters rapidly activate low affinity receptors at the postsynaptic neuronal membrane and diffuse outside the synaptic cleft to activate high affinity receptors at the astrocytic membrane. (C) Gliotransmitters activate high affinity receptors at perisynaptic locations in the neuronal membrane. Neurotransmitter (B) or gliotransmitter (C) decreasing concentrations over distance from release sites is illustrated by different color intensity.

Figure 2. Synaptic Modulatory Actions of Gliotransmitters Depend on Integration by Astrocytes of the Ca²⁺ Changes Evoked by Different Levels of Neuronal Activity

(A) Low levels of synaptic activity (blue arrow, left) evoke rapid, spatially restricted Ca²⁺ elevations at an astrocytic process (red trace) resulting in a gliotransmitter release that locally modulates synaptic transmission (green arrow, right) (Jourdain et al., 2007; Perea and Araque, 2007; Pascual et al., 2012; Santello et al., 2011; Panatier et al., 2011). The change in synaptic efficacy due to gliotransmitter-mediated regulation of the probability of release is illustrated as an increase in the mean amplitude of excitatory postsynaptic events(dashed and solid blue line). (B) Ca²⁺ elevations evoked at an astrocytic process by an intense activity of an individual synapse diffuse to a nearby process (red arrow) to trigger gliotransmitter release that affects nearby synapses (right). The red superimposed traces are the integrated Ca²⁺ response (solid line) and the elementary Ca²⁺ response (dashed line, same as solid line in A). As a result of this astrocyte modulatory action, synaptic transmission (solid blue line) can be either potentiated (Navarrete and Araque, 2010) or depressed (Zhang et al., 2003; Pascual et al., 2005; Andersson et al., 2007; Serrano et al., 2006)(dashed blue line in a and b, respectively). As in (C), the focus of the phenomenon being described is indicated in colour, while the elements that are not the focus are greyed out (but are not necessarily inactive). (C) Multiple Ca²⁺ events at different processes evoked by simultaneously active synapses are spatially and temporally integrated (left) resulting in a global, long lasting Ca²⁺ elevation that can affect synaptic transmission in the territory of individual astrocytes (right) (Henneberger et al., 2010). The global Ca²⁺ response (solid line) and the integrated Ca²⁺ response (dashed line, same as solid line in B) are reported. Note the different time scale of Ca²⁺ traces in (A), (B) and (C).