Glial-neuronal interactions--implications for plasticity and drug addiction

Abstract

Among neuroscientists, astrocytes have for long played Cinderella to their neuron stepsisters. While the importance of glia in regulating brain activity was predicted by Ramon y Cajal more than a century ago (Garcia-Marin et al., Trends. Neurosci. 30:479-787, 2007), these cells, until recently, have been thought to play mainly a passive part in synaptic signaling. Results obtained over the last decade have begun to suggest otherwise. Experiments carried out in a number of labs have shown that glial cells, especially astrocytes, directly participate in synaptic signaling and potentially regulate synaptic plasticity and network excitability. The presence of signaling pathways on astrocytes that are analogous to those at presynaptic terminals suggests a role for these cells in network plasticity. Findings that the same signaling pathways can be activated by receptors for drugs of abuse present on astrocytes suggest a role for these cells in the addictive process. In this review, we summarize current understanding of astrocytic role in synaptic signaling and suggest that a complete understanding of the process of addiction requires a better understanding of the functional role of these cells.

Fig. 1

Signaling at a tripartite glutamatergic synapse. a A single astrocyte (cyan, labeled A) sends out processes that envelop or are in close proximity to a number of synapses. Postsynaptic neuron and its dendrite (red, labeled N); presynaptic axon and bouton (green). b Both astrocytes and the postsynaptic neuron respond to released glutamate at a synapse. Glutamate release from the presynaptic terminal acts on the ionotropic glutamate receptors (blue rectangles) at the postsynaptic membrane (red) and on mGluRs (blue cylinders) on the astrocytic membrane (cyan). Activation of mGluRs on astrocytes initiates an intracellular calcium wave that propagates down the length of the astrocytic processes. c Astrocytes have a form of excitability mediated by calcium signals. An example of a mechanism for intracellular propagation of calcium waves. Activation of astrocytic P2Y receptors (blue rectangles) activates the phospholipase C signaling cascade to produce IP₃ as a second messenger. Released IP₃ acts on its receptors on the ER (green ovals) to release calcium from stores. Calcium thus released can either modulate the activation of IP₃Rs by ambient level of IP₃, or activate Phospholipase C to increase production of the second messenger. At the same time, release of ATP from the astrocyte acts as a regenerative mechanism for the propagation of calcium signals via progressive activations of P2YRs down the astrocytic soma and processes. d Astrocytes can release transmitters to talk back to neurons. An example of astrocyte to neuron communication. Activation of an astrocyte by synaptically released glutamate can, in turn, trigger release of the transmitter from astrocytic vesicles (cyan circles) back on the postsynaptic neuron. One mechanism by which this communication can occur is via the activation of extrasynaptic NMDA receptors (blue cylinders) on the postsynaptic dendrite. This would be a distinct mechanism from the presynaptic release of glutamate (green vesicles) acting on synaptic ionotropic glutamate receptors (blue rectangles)

Fig. 2

Putative mechanism for the action of nicotine via astrocytes. a Activation of calcium signaling by nicotine. Astrocytes possess functional α7-nAChRs. Activation of these receptors by nicotine results in calcium influx into the astrocyte which, in turn, triggers calcium-induced calcium release via the opening of RyRs on the ER calcium stores. These signals can further be amplified by the subsequent activation of IP₃Rs and release of ATP as shown in Fig. 1c. b Hypothetical modulation of neuronal networks by nAChRs on astrocytes. Astrocytes (denoted by A), via their numerous processes and proximity to synapses, exert local influence on neuronal activity, possibly by synchronizing the activity of a small groups of neurons (denoted by N). Activation of nAChRs on astrocytes coordinates calcium oscillations across a group of astrocytes, in turn modulating network activity across a larger area