Glial Development
4.1 Phylogeny of glia and evolutionary specificity of glial cells in human brain
Glia appear early in phylogeny; even primitive nervous systems of invertebrates such as annelids and leeches, crustacea and insects, and molluscs and cephalopods contain clearly identifiable glial cells, and their study has provided a signifi- cant contribution to our understanding of glial cell physiology. Most strikingly, however, the evolution of the CNS is associated with a remarkable increase in the number and complexity of glial cells (Figure 4.1). In the leech, for example, the nervous system is organized in ganglia; each ganglion contains 20–30 neurones, which are coupled to one giant (up to 1 mm in diameter) glial cell. The nervous system of the nematodeCaenorhabditis eleganscontains 302 neurones and only 56 glial cells (i.e. glia account for about 16 per cent of all neural cells). In drosophila, glial cells already account for∼20–25 per cent of cells in the nervous system, and in rodents about 60 per cent of all neural cells are glia.
In human brain, glial cells are certainly the most numerous as it is generally believed that glial cells outnumber neurones in human brain by a factor of 10 to 50; although the precise number of cells in the brain ofHomo sapiens remains unknown. Early estimates put a total number of neurones at∼85 billion; however, now we know that this number should be substantially larger as a cerebellum alone contains ∼105 billion neurones. Therefore, the human brain as a whole may contain several hundred billions of neurones and probably several trillions (or thousand billions) of astrocytes. Morphological data for the cortex are more reliable and they show that human brain has the highest glia to neurone ratio among all species (this ratio is 0.3:1 in mice and about 1.65:1 in human brain – see Figure 4.1). Interestingly, however, the overall volume of the glial compartment remains more or less constant as they occupy about 50 per cent of the nervous system throughout the evolutionary ladder.
Not only does the human brain have the largest number of glia, but the glial cells in primates also show remarkable differences compared to nonprimates. The
Glial Neurobiology: A Textbook Alexei Verkhratsky and Arthur Butt
© 2007 John Wiley & Sons, Ltd ISBN 978-0-470-01564-3 (HB); 978-0-470-51740-6 (PB)
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Figure 4.1 Phylogenetical advance of glial cells:
A. Percentage of glial cells is increased in phylogenesis. In fact the total quantity of neural cells in the brain of higher primates, includingHomo sapiens, is not known precisely; the number of neurones in human brain can be as high as several hundred of billions. It is commonly assumed that glia outnumber neurones in human brain by a factor of 10 to 50 (e.g. Kandel, Nerve cells and behaviour. In:Principles of neural science, Kandel ER, Schwartz JH, Jessell TM, Eds, 4th edition, pp. 19–35. New York: McGraw-Hill) although the precise ratio remains to be determined.
B. The numbers of glia and neurones in cortex is more precisely quantified, and this graph shows the glia/neurone ratio in cortex of high primates; this ratio is the highest in humans. (Data are taken from Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI, Goodman M, Redmond JC, Bonar CJ, Erwin JM, Hof PR (2006) Evolution of increased glia–neuron ratios in the human frontal cortex.Proc Natl Acad Sci U S A103, 13606–13611).
C. Graphic representation of neurones and astroglia in mouse and in human cortex. Evolution has resulted in dramatic changes in astrocytic dimensions and complexity.
D. Relative increase in glial dimensions and complexity during evolution. Linear dimensions of human astrocytes when compared with mice are ~2.75 times larger; and their volume is 27 times larger; human astrocytes have ~10 times more processes and every astrocyte in human cortex enwraps ~20 times more synapses.
(C, D – adapted from Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain.Trends Neurosci29, 547–553)
4.1 EVOLUTIONARY SPECIFICITY OF GLIAL CELLS IN HUMAN BRAIN 31 most abundant astroglial cell in human and primate brain are the protoplasmic astrocytes, which densely populate cortex and hippocampus. Human protoplasmic astrocytes are much larger and far more complex than protoplasmic astrocytes in rodent brain. The linear dimensions of human protoplasmic astroglial cells are about 2.75 times larger and have a volume about 27 times greater than the same cells in mouse brain. Furthermore, human protoplasmic astrocytes have about 40 main processes and these processes have immensely more complex branching than mouse astrocytes (which bear only 3–4 main processes). As a result, every human protoplasmic astrocyte contacts and enwraps∼two million synapses compared to only 90 000 synapses covered by the processes of a mouse astrocyte.
Moreover, the brain of primates contains specific astroglial cells, which are absent in other vertebrates (Figure 4.2). Most notable of these are the interlaminar astrocytes, which reside in layer I of the cortex; this layer is densely populated by synapses but almost completely devoid of neuronal cell bodies. These interlaminar astrocytes have a small cell body (∼10m), several short and one or two very long processes; the latter penetrate through the cortex, and end in layers III and IV; these processes can be up to 1 mm long. The endings of the long processes create a rather unusual terminal structure, known as the ‘terminal mass’ or ‘end bulb’, which are composed of multilaminal structures, containing mitochondria.
Most amazingly, the processes of interlaminar astrocytes and size of ‘terminal masses’ were particularly large in the brain of Albert Einstein; although whether these features were responsible for his genius is not really proven. The function of these interlaminar astrocytes remain completely unknown, although it has been speculated that they are the astroglial counterpart of neuronal columns, which are the functional units of the cortex, and may be responsible for a long-distance signalling and integration within cortical columns. Quite interestingly, interlaminar astrocytes are altered in Down syndrome and Alzheimer’s disease.
Human brain also contains polarized astrocytes, which are uni- or bipolar cells which dwell in layers V and VI of the cortex, quite near to the white matter; they have one or two very long (up to 1 mm) processes that terminate in the neuropil.
The processes of these cells are thin (2–3 m in diameter) and straight; they also have numerous varicosities. Once more, the function of polarized astrocytes remains enigmatic; although they might be involved in para-neuronal long-distance signalling.
Most interestingly, the evolution of neurones produced fewer changes in their appearance. That is, the density of synaptic contacts in rodents and primates is very similar (in rodent brain the mean density of synaptic contacts is ∼1397 millions/mm3, which is not very much different from humans – synaptic density in human cortex is around 1100 millions/mm3). Similarly, the number of synapses per neurone does not differ significantly between primates and rodents. The shape and dimensions of neurones also has not changed dramatically over the phylogenetic ladder: human neurones are certainly larger, yet their linear dimensions are only
∼1.5 times greater than in rodents.
Thus, at least morphologically, evolution resulted in far greater changes in glia than in neurones, which most likely has important, although yet undetermined, significance.
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Figure 4.2 Astrocytes of human cortex. Schematic representation of human cortical layers, I to VI. Primate-specific astrocytes are (1) the interlaminar astrocytes, somatas of which reside in Layer I, and processes extend towards layers III and IV, and (2) polarized astrocytes, which are localized in layers V and VI and also send long processes through the cortical layers. Human protoplasmic astrocytes are characterized by a very high complexity of their processes. White matter contains fibrous astrocytes, which are least different from nonprimates. (Modified from Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain.Trends Neurosci29, 547–553)