Astrocytes: more than just glue

The major cellular component of the human brain is notneurons, at least in numerical terms, but glial cells, especiallyastrocytes. The astrocyte-to-neuron ratio and astrocyte struc-tural complexity have both increased as the brain has evolved,with the former reaching 10:1 in humans.1,2 Classically, brainfunction has been perceived as entirely neuronal, with the glia(derived from the Greek word for glue) playing subordinateroles: oligodendrocytes in myelination, microglia in macro-phage function, and astrocytes in supporting and nourishingneurons. However, it is now likely that astrocytes have a moremajor role in neurological function and disease than previouslythought.

Astrocytes, like neurons, vary enormously in shape and sizein different areas of the brain, but only recently has this (likeneurons again) been thought to reflect differing functions.They influence the anatomy of specific brain areas, especiallyduring development and neuronal migration. They closelycontrol brain homeostasis, forming part of the blood–brainbarrier and controlling regional blood flow, as well as the ionicand molecular micro-environment.1–4 Disorders directly orindirectly related to astrocytes are increasingly recognized aswell including, amongst others, leukodystrophies (Alexanderdisease, megaloencephalic leukoencephalopathy with subcorti-cal cysts, and vanishing white matter); neurodegenerative con-ditions such as Huntington and Parkinson diseases; acute andchronic metabolic conditions such as hepatic encephalopathy,Niemann-Pick type C, or acaeruloplasminaemia; chronic painsyndromes; and neuromyelitis optica (aquaporin 4 is mainlyexpressed in astrocytes). Reactive astrogliosis is an importantpathological response to injury that amongst other effects pre-vents axonal migration. There is a suspected role in epilepsyand migraine as well.1–4

The biggest current controversy concerns gliotransmissionand the astrocyte’s role in information transfer. Astrocytes havethousands of processes which connect closely to neurons, inparticular to neuronal synapses. These are dynamic as they canchange in shape and size over time. The tripartite hypothesissuggests that these astrocyte processes have important influ-ences on synaptic function.3 In vitro astrocytes take up andsecrete neurotransmitters (especially glutamate which is theprime excitatory molecule in the brain), express similar ionchannels to adjacent neurons, and control calcium signalling.Knockout mice without glutamate uptake channels develop a

severe neonatal epileptic encephalopathy.4 Over the longerterm, astrocytes also appear to influence synapse formationand pruning. As astrocytes form syncytia with gap junctionsthat allow cell-to-cell transport (e.g. of calcium), it is also pos-sible that astrocytes influence multiple synapses in contact withthe same or adjacent astrocytes, and play a role in coordinatedneuronal discharges.3 Such roles could include intrinsic bio-rhythms such as sleep–wake cycles.5 Again, knockout micewithout these gap junctions die, although from probable car-diorespiratory failure.4 Finally, astrocytes secrete agents suchas ATP or serine which in vivo can affect adjacent neurons andother astrocytes and are thus putative ‘gliotransmitters’.

Until recently the exact contribution all this actually makesto brain function was very uncertain as most had only beendemonstrated in cell culture or other rather artificial circum-stances. However, last year for the first time it was convinc-ingly demonstrated in an animal model that glia can influencerespiratory control. While blood carbon dioxide (pCO2) andpH levels have been known to affect respiratory drive for dec-ades, the exact mechanism has remained unclear. Acid-sensi-tive neurons in certain brainstem nuclei have been believed tobe responsible, although the precise ion channels have notbeen identified. In fact, connexin 26 hemichannels in brain-stem glial cells have been found to be directly sensitive topCO2 levels. In response the glia then secrete ATP which inturn affects neurons that control respiration. Blocking thesehemichannels reduces the ventilatory response to increasedpCO2 by up to 25%.6 More recently, reducing gliotransmitterfunction in another knockout mouse model has been shown toaffect hippocampal memory processes.7

The relevance of gliotransmission to higher brain functionsstill needs a lot of research, but these new insights have obvi-ous implications for neurodevelopmental disorders. In thera-peutic terms, strategies aimed at astrocytes could be importantin acquired brain insults such as trauma and stroke, and per-haps in other disorders previously considered entirely neuro-nal such as epilepsy. The brain is even more complex thanpreviously imagined.

PETER BAXTEREditor in Chief

doi: 10.1111/j.1469-8749.2011.04232.x

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ª The Author. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press 291

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY EDITORIAL