Astrocytes: Part Two: The Third Element

Abstract

Part One described the astrocyte as a metabolic partner. This part covers the harder claim: that astrocytes participate in signalling, release transmitters of their own, and can tell one neural pathway from another.

A 2019 review in Neuroscience by Caitlin Durkee and Alfonso Araque sets out the evidence, and its central line is worth stating early: astrocytes do not simply follow synaptic activity; they process and integrate synaptic information into diverse and plastic responses.

It is also candid that the phenomenon has been doubted, and about why the methods make it hard to settle.

1.The Tripartite Synapse

The standard picture of a synapse has two elements: a presynaptic terminal releasing transmitter, a postsynaptic membrane receiving it. The tripartite synapse concept adds a third — the astrocytic process wrapping the cleft — as an integral element of synaptic function rather than an onlooker.

The claim is bidirectional. Astrocytes respond to synaptically released neurotransmitters, and they release gliotransmitters that affect neuronal activity in return.

The gliotransmitters identified include glutamate, D-serine, ATP and adenosine, GABA and neuropeptide Y. The authors note that evidence remains sparse for astrocyte responsiveness to dopamine, histamine, serotonin and opioids — an honest gap, given how much of psychopharmacology runs through those systems.

2.Calcium, in Pieces

Astrocytes do not fire action potentials. Their signalling currency is calcium, elevated through mobilisation from intracellular stores via G-protein-coupled receptors and through transmembrane flux via TRP channels.

The important structural fact is that these elevations are spatially restricted. They occur in microdomains — small compartments within a single astrocyte, which may contact many thousands of synapses.

Compartmentalisation is what makes specificity possible at all. A cell responding as a single unit could only signal globally; a cell with independently active microdomains can, in principle, respond differently at different synapses.

3.Integration, Not Relay

The evidence that astrocytes compute rather than transmit comes from what happens under combined input.

When hippocampal astrocytes received simultaneous glutamatergic and cholinergic stimulation, the calcium response was diminished relative to what linear summation would predict. The two signals interacted rather than adding.

And the interaction was selective: it occurred for glutamate paired with acetylcholine, but not for glutamate paired with GABA. The authors read this as integration occurring through interaction of intracellular pathways rather than at the receptors.

Subsequent work found astrocyte responsiveness is itself plastic. Stimulating parvalbumin-expressing versus somatostatin-expressing interneurons produced differential astrocyte calcium responses, depending on co-activation of particular GABA and neuropeptide receptors.

4.Telling Pathways Apart

Three findings in this review go beyond specificity and into discrimination.

In the central amygdala, ATP and adenosine released from the same astrocyte could both excite and depress synaptic transmission depending on the circuit — suppressing excitatory inputs through presynaptic A1 receptors while enhancing inhibitory inputs through A2A receptors. One cell, one transmitter, opposite effects, determined by which circuit was receiving it.

In the dorsal striatum, subsets of astrocytes selectively interact with medium spiny neurons belonging to the two main corticostriatal circuits. They respond to activity of either the direct or the indirect pathway, and in turn selectively modulate synapses belonging to that same pathway.

And a single hippocampal astrocyte releases different gliotransmitters depending on the intensity of what it receives: low-frequency GABAergic input triggers glutamate release, enhancing transmission, while high-frequency stimulation produces a biphasic response involving both glutamate and ATP or adenosine, with opposing effects.

The direct and indirect striatal pathways are the two arms of basal ganglia control, with roughly opposite functional consequences. An astrocyte that can address them separately is not providing support. It is addressing a circuit.

5.Why This Is Still Contested

The authors state the dispute plainly: some reports have raised doubt about the mechanisms and the physiological role of gliotransmission.

Their methodological caution is more useful than the dispute itself. Astrocytes undergo strong phenotypic changes in culture, which means the actual existence and physiological relevance of responses observed in cultured cells may be compromised. A great deal of early gliotransmission work was done in culture.

Their unresolved list is specific: whether integration across neurotransmitter types occurs within single astrocytes generally, what the functional consequences of circuit-specific astrocyte signalling are for basal ganglia function, and what determines which gliotransmitter a single astrocyte releases on a given occasion.

All of it is rodent — slices, cultures, and genetically modified mice. There is no human counterpart to any of these experiments.

6.Three Jobs, One Cell

Read alongside the rest of this section, the astrocyte now has three roles that were each discovered separately.

It supplies neurons with metabolic substrate, and memory fails when that supply is blocked — Part One. It releases transmitters and discriminates between pathways — this part. And in our series on synaptic pruning, astrocytes were found to eliminate synapses, preferentially excitatory ones, through the same complement tag microglia use.

Fuel, signal, and structural editing, in a cell that textbooks classified as glue. The name astrocyte comes from its shape; the name glia comes from the Greek for glue, which is what the tissue was assumed to be.

Editorial Comment

MindHeaven® makes no claim relating to astrocytes, gliotransmission or any of the mechanisms described here, and nothing in our formulations is proposed to act on them.

We should also record what we could not do. This topic was filed with three sources; one — a 2021 review of astrocyte–neuron metabolic cooperation in Cell Metabolism — proved unobtainable. The publisher link redirects, the PubMed Central identifier resolves to a different article, and the university repository copy that Unpaywall lists carries an embargo running to 2099. We have written only from the two reviews we read in full, and this series would be better with the third.

The reason to publish it anyway is that the astrocyte is the clearest case in neuroscience of a component being misclassified because of what it looked like. That is worth knowing before reading any claim about the brain that begins by counting neurons.