Nature Reviews Neuroscience - Review
March 2001 Vol 2 No 3 REVIEW
Nature Reviews Neuroscience 2, 185 -193 (2001); doi:10.1038/35058528
GLIA: LISTENING AND TALKING TO THE
SYNAPSE
Philip G. Haydon about the author
Preface
Glial cells are emerging from the background to become more
prominent in our thinking about integration in the nervous system.
Given that glial cells associated with synapses integrate neuronal
inputs and can release transmitters that modulate synaptic activity,
it is time to rethink our understanding of the wiring diagram of the
nervous system. It is no longer appropriate to consider solely
neuron­neuron connections; we also need to develop a view of the
intricate web of active connections among glial cells, and between
glia and neurons. Without such a view, it might be impossible to
decode the language of the brain.
Summary
Glial cells have been largely regarded as merely the supportive elements
in the nervous system. However, recent evidence indicates that the glia have
an active role in modulating synaptic transmission. In fact, communication
between neurons and glia is bidirectional, as neuronal activity can elicit
changes in glial calcium levels.
Different molecules released by neurons can affect intracellular Ca2+
levels in glial cells. Glutamate has received a lot of attention in this regard,
and it has been shown to modulate glial Ca2+ levels both in culture and in
situ.
The increases in Ca2+ levels experienced by individual glial cells can
propagate across large distances in the form of Ca2+ waves. The mechanism
of propagation seems to involve both intracellular and extracellular signals
(inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) and ATP, respectively). It is
likely that Ins(1,4,5)P 3 diffusion through gap junctions is important for short-
range wave propagation, whereas ATP might be more relevant for
propagation across larger distances.
ATP is not the only transmitter released by astrocytes. This cell type can
also release glutamate in a calcium-dependent manner that probably
involves exocytosis. D-serine is another molecule released by astrocytes,
although its release mechanism is not known. Similarly, the pathway
responsible for ATP release remains to be discovered but is unlikely to
involve vesicle fusion.
Transmitters released by astrocytes can modulate synaptic transmission,
giving rise to the concept of 'tripartite synapses'. Evidence regarding this
modulation has been obtained both in culture and in situ, and it seems to
affect basal synaptic transmission, as well as plastic phenomena. Moreover,
glial cells can also modulate neuronal activity through a direct pathway that
involves gap junctions between neurons and glia.
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Nature Reviews Neuroscience - Review
The reciprocal communication between neurons and glia adds degrees of
freedom to brain function. For example, increases in astrocytic calcium
elicited by the activity of a given synapse could affect the function of
synapses at distant locations through the spread of the calcium signal within
the same astrocyte. Is this phenomenon ever observed in situ ? What are the
functional consequences of this lateral, much slower, signalling pathway?
Future experiments will aim to address these questions.
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 2001 Nature Publishing Group
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