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Neurochemistry International 57 (2010) 332–343 Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/neuint Physiology of neuronal–glial networking Alexei Verkhratsky a,b,* a Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester, UK b Institute of Experimental Medicine, ASCR, Prague, Czech Republic ARTICLE INFO ABSTRACT Article history: Neuronal–glial networks are the substrate for the brain function. Evolution of the nervous system Received 5 November 2009 resulted in the appearance of highly specialized neuronal web optimized for rapid information transfer. Received in revised form 5 January 2010 This neuronal web is embedded into glial syncytium, thereby creating sophisticated neuronal–glial Accepted 1 February 2010 circuitry were both types of neural cells are working in concert, ensuring amplification of brain Available online 6 February 2010 computational power. In addition neuroglial cells are fundamental for control of brain homeostasis and they represent the intrinsic brain defence system, being thus intimately involved in pathogenesis of Keywords: neurological diseases. Glia ß 2010 Elsevier Ltd. All rights reserved. Astrocytes Glutamate receptors Purinoceptors Neuronal–glial signalling How does the brain work? How did the intellect evolved? Why 1. Neuronal–glial circuits form the nervous system human being is so different from the beast? How do we think? These questions represent the most formidable challenge the 1.1. Neuroglia: the beginning natural sciences ever faced. The evolution of the nervous functions went from single neurones loosely connected into the diffuse The cell, as the basic unit of the life, was initially discovered by nervous system through the first conglomerates of neural cells Robert Hooke (who also contemplated the name) in 1665 (Hooke, assembled into ganglia to the centralized nervous system. In the 1665). At the very same time, the live cells were also observed by a latter much greater degree of specialization and diversity was brilliant microscopist Antonius van Leeuwenhoek, who described achieved, thus allowing the emergence of the intellect. In the single-cell algae, protists, bacteria (whom he called animalcules or course of the evolution the primary elements of the brain, the little animals), red blood cells and was the first to observe the neural cells, have diversified, thus giving rise to several cellular movements of spermatozoids (Leeuwenhoek, 1673/1696). It took, populations, which are responsible for different functions. At the however, another 150 years before the cell theory was introduced very early phylogenetic stages the neural cells were broadly by Theodor Schleiden and Matthias Jakob Schleiden (Schwann and divided into electrically excitable neurones and electrically non- Schleyden, 1847) and was subsequently refined and generalised by excitable glia; these two types of cells developed further and Rudolf Virchow. formed extremely heterogeneous and functionally specialised It was also Rudolf Virchow who, in the mid 1850s, developed populations. These cellular populations in turn form the intricate the concept of neuroglia, as a connective tissue, which ‘‘...holds neural circuitry, connected through chemical synapses or inter- them (nervous elements) together and gives the whole its form...’’ cellular gap junctions. The connectivity of this neural circuitry is (Virchow, 1856, 1858); for history of glia see also (Kettenmann and the raison d’etre of the nervous system because it allows the flow of Verkhratsky, 2008; Verkhratsky, 2006b). Virchow regarded the information that is analysed, processed, stored and used in the neuroglia exclusively as a connective tissue; the cellular nature of decision making and cognition. The failure of the connectivity in glia, however, was soon to be acknowledged. Incidentally, the first the neural web results in nervous system malfunction, being thus glial elements were described even before Virchow’s ideas were the substrate of neurological diseases. promulgated, as indeed already in 1838 Robert Remak found the covering sheath around nerve fibres (Remak, 1838), and in 1851 Heinrich Mu¨ ller produced the first images of retinal radial glia (the cells which were subsequently named Mu¨ ller cells by Albert * Tel.: +44 0161 2757324. Ko¨llicker (Ko¨lliker, 1852)). Slightly later Karl Bergmann had E-mail address: [email protected]. identified radial glial cells in the cerebellum (Bergmann, 1857) 0197-0186/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2010.02.002 A. Verkhratsky / Neurochemistry International 57 (2010) 332–343 333 and Otto Deiters described the stellate glial cells (Deiters, 1865). system is organized in ganglia; each ganglion contains 20–30 The introduction of staining techniques, and particularly the neurones, which are linked to one giant (up to 1 mm in diameter) development of ‘‘reazione nera’’ or black staining technique (Golgi, glial cell. The nervous system of the nematode Caenorhabditis 1873), see also (Golgi, 1903) greatly facilitated visualisation of elegans contains 302 neurones and only 56 glial cells (i.e. glia neural cells in their entirety. Very soon, multiple types of glia were account for about 16% of all neural cells). In Drosophila, glial cells described in the brain and in the spinal cord of humans and other already represent 20–25% of cells in the nervous system, and in mammals. In 1891 the stellate glia was christened astrocytes by rodents about 50–60% of all neural cells belong to glia. In the Michael von Lenhossek (Lenhossek, 1891), although it took human brain, glial cells are certainly the most numerous another 30 years before oligodendrocytes and microglia, discov- outnumbering neurones by a factor of 10. Simultaneously, the ered by Pio del Rio Hortega (Rio-Hortega, 1919, 1921, 1932) evolution of primate nervous system resulted in significant became legitimate members of neural tissue. morphological changes in astroglial cells. The size of human The expansion of knowledge about glia coincided with long- protoplasmic astrocyte is about 2.5–3 times larger as compared lasting conflict between reticular (led by Camillo Golgi) and with the same astrocyte from rodent brain; in addition human neuronal (championed by Santiago Ramon y Cajal) theories of protoplasmic astrocytes have 10 times more primary processes, brain organisation, which came to the climax in 1906 when both and correspondingly much more complex processes arborisation. Golgi and Cajal were awarded the Nobel prise; their lectures, As a result, human protoplasmic astrocyte contacts and integrates delivered in Stockholm on December 10–13, 1906, were specifi- 2 millions of synapses residing in its territorial domain, whereas cally dedicated to the neuronal/reticular controversy. The neuronal rodent astrocytes cover 20.000–120.000 synaptic contacts theory was victorious and rapidly gained general appreciation (Oberheim et al., 2006). Similarly, human fibrous astrocytes (Ramon y Cajal, 1952); very soon the neuronal networks start to be dwelling in the white matter are 2.2 times larger than in rodents regarded as the sole substrate for brain integration and informa- (Oberheim et al., 2009). Furthermore, the cortex of primates tion processing, whereas glia was downgraded to the position of contains several specific types of astroglia such as the interlaminar supporting tissue where it humbly remained for next 80 years. Last and polarised astrocytes (Oberheim et al., 2009). decades of 20-ies century, however, signalled the renaissance in glial research; recent discoveries have shaken the foundations of 1.3. The micro-architecture of the brain: astrocytes form the neuronal doctrine by demonstrating the active involvement of glial neurovascular unit cells into synaptic transmission as well as vital role of glia in controlling brain homeostasis and defence (Araque, 2008; Araque The human brain is arguably the most complicated living et al., 1999; Fellin et al., 2004; Halassa et al., 2007, 2009; Perea and system that ever existed; and indeed the complexity of the neural Araque, 2005; Verkhratsky, 2006a, 2009; Verkhratsky and Toescu, cellular circuitry is quite extraordinary. The neural cells are 2006; Volterra and Meldolesi, 2005). These discoveries facilitate exceedingly densely packed within a strictly limited volume of the further evolution in our understanding of the brain function, skull, thus requiring a great precision in regulation of brain calling for a more inclusive doctrine that regards neuronal–glial homeostasis at the different stages of early development and circuitry as a substrate for intelligence and brain function. postnatal remodelling. Furthermore, the brain is a precious asset, and as such it is separated from the rest of the body by the brain– 1.2. Phylogenetic advance of glia blood barrier which limits the impact of bodily homeostatic systems on the nervous system. The brain tissue shows a high The glial cells appeared early in evolution, being, similarly to degree of hierarchical organization, with anatomical segregation of neurones, the descendants of epithelial cells (Reichenbach and different types of cells with different functions. The basic element Pannicke, 2008). These ancestral epithelial cells already developed of this hierarchical structure is formed by glial cells, which primitive exocytotic machinery, as well as the system of essentially divide the brain parenchyma into morphologically intercellular

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