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Preface
List of abbreviations
Physiology of Glia
Introduction to Glia
- Founders of glial research: from Gabriel Valentin to Karl-Ludwig Schleich
- Beginning of the modern era
- Changing concepts: Glia express molecules of excitation
- Glia and neurones in dialogue
The bottom panel shows original images of glial cells drawn by Ramón y Cajal: ‘Neuroglia of the superficial layers of the cerebrum; two-month-old child. Another theory (proposed by Carl Weigert) viewed glial cells as merely structural elements of the brain, filling the space not occupied by neurons.
General Overview of Signalling in the Nervous System
Intercellular signalling: Wiring and volume modes of transmission
These discoveries led to the emergence of a new theory of cell-to-cell signaling in the nervous system, which combines highly localized signaling mechanisms (through chemical and electrical synapses), generally termed a 'wiring'. Adapted and modified from Sykova E (2004) Extrasynaptic volume transmission and diffusion parameters in the extracellular space. Neuroscience Zoli M, Jansson A, Sykova E, Agnati LF, Fuxe K (1999) Volume transmission in the CNS and its relevance to neuropsychopharmacology.Trends Pharmacol Sci.
Intracellular signalling
Metabotropic receptors coupled to PLC produce the secondary messengers InsP3 (inositol-1,4,5-trisphosphate) and DAG (diacylglycerol) from PIP2 (phopshoinositide diphosphate), e.g. The G proteins can also be connected to plasmalemmal channels, and often activation of metabotropic receptors triggers opening of the latter.
Morphology of Glial Cells
- Astrocytes
- Oligodendrocytes
- NG2 expressing glia
- Schwann cells
- Microglia
Tanycytes are specialized astrocytes found in the periventricular organs, the pituitary gland, and the raphe portion of the spinal cord. Oligodendrocytes also participate in the development of the nodes of Ranvier and determine their periodicity (see Chapter 8).
Glial Development
- Phylogeny of glia and evolutionary specificity of glial cells in human brain
- Macroglial cells
- Astroglial cells are brain stem cells
- Schwann cell lineage
- Microglial cell lineage
In the cerebellum, some Bergmann glia and other astrocytes arise from radial glia (some of which share a lineage with Purkinje neurons), and later in development, glial progenitors migrate from the dorsal region to IV. ventricle to give rise to all types of cerebellar astrocytes, myelinating oligodendrocytes and NG2-glia (as well as interneurons). Fetal macrophages are identified in the neuroepithelium at a very early stage (~8 embryonic day in rodents).
General Physiology of Glial Cells
Membrane potential and ion distribution
Ion channels
These channels determine the resting membrane potential; the Kir channels are regulated by extracellular K+ concentration, and increases in the latter result in an inward flow of K+ ions, which is important for the removal of K+ from the extracellular space, which is considered a primary physiological function of astrocytes (see Chapter 7). NaV channels are somehow involved in the control of glial cell proliferation, differentiation or migration.
Receptors to neurotransmitters and neuromodulators
- Glutamate receptors
- Purinoreceptors
- GABA receptors
- Cytokine and chemokine receptors
- Complement receptors
- Endothelin receptors
- Platelet-activating factor receptors
- Thrombin receptors
AMPA receptors are present in astroglial cells in most of the brain regions, such as cortex, hippocampus, cerebellum and retina. Several types of P2X receptors are expressed in microglial cells; particularly important are P2X7 receptors, which are activated by high (>1 mM) ATP concentrations.
Glial syncytium – gap junctions
Astroglial cells in the CNS have the highest density of gap junctions (at a molecular level, astrocytes mainly express Cx43, Cx30 and Cx26) and thus the highest degree of intercellular coupling. However, the networks formed by gap junctions are not absolutely ubiquitous and the degree of connectivity varies considerably between different brain regions. This integration also extends to ependymal cells, as the latter form gap junctions with astrocytes and also with other ependymocytes (Figure 5.8).
Glial calcium signalling
- Cellular Ca 2+ regulation
- Glial Ca 2+ signalling – endoplasmic reticulum takes the leading role
- Propagating calcium waves as a substrate of glial excitability In physiological conditions, glia are stimulated by relatively brief and local expo-
Calcium homeostasis and the calcium signaling system result from the concerted interaction of Ca2+ channels (which include plasmalemmal ion channels, ionotropic receptors, and intracellular Ca2+ channels), Ca2+ transporters (Ca2+ pumps and Na+/Ca2+ exchangers, NCX), and cellular Ca2+ buffers . A considerable amount of Ca2+ is also removed from the cytosol by active uptake into the lumen of the ER via the SERCA pumps (Sarco(Endo)plasmic Reticulum Ca2+ .ATPases) located in the endomembrane. Ca 2+ entry pathways in mature glial cells are represented by several types of Ca 2+ permeable ligand-gated channels (most notably by ionotropic glutamate and P2X purinoreceptors) and store-operated Ca 2+ channels.
Neurotransmitter release from astroglial cells
- Nonvesicular release of neurotransmitter from astrocytes Several types of neurotransmitters, including glutamate, ATP and aspartate,
- Vesicular release of neurotransmitter from glial cells
Volume-activated anion channels provide a pathway for the release of glutamate and other negatively charged amino acids such as taurine. Most importantly, astroglial glutamate release in response to elevated intracellular Ca2+ has been directly demonstrated. As a result, vesicular release of neurotransmitter from astroglial cells develops significantly more slowly compared to neurons.
Glial neurotransmitter transporters
- Astrocyte glutamate transporters
- Astrocyte GABA transporters
- Astrocyte glycine transporters
- Other neurotransmitter transporters
The performance of glutamate transporters clearly depends on the transmembrane concentration gradients of Na + and K + ; an increase in intracellular Na+ as well as an increase in extracellular K+ inhibits glutamate transport. GABA transporters use the electrochemical gradient for Na+, and translocation of one GABA molecule requires a cotransport of two Na+ ions. Glycine translocation by GlyT1 is coupled with cotransport of 2 Na+ and 1 Cl−, whereas GlyT2 requires cotransport of 3 Na+ and 1 Cl−.
Glial cells produce and release neuropeptides
Galanin Oligodendrocyte precursors Galanin expression is controlled by thyroid hormone; galanin may be involved in regulating the growth and differentiation of neurons and oligodendrocytes.
Glial cell derived growth factors
In the first case, glia-derived growth factors regulate various aspects of differentiation, growth and development of nerve cells. Astrocytes are the most prolific producers of growth factors; oligodendrocytes produce much less, but importantly they release netrin-1, which directs axonal pathfinding (and which is absent in astrocytes). Neuronal injury greatly increases the production and release of growth factors, particularly from reactive astrocytes and activated microglial cells.
Neuronal–Glial Interactions
- Close apposition of neurones and astroglia: the tripartite synapse
- Neuronal–glial synapses
- Signalling from neurones to astrocytes
- Signalling from astrocytes to neurones
- Signalling between oligodendrocytes and neurones
- Signalling between Schwann cells and peripheral nerves and nerve endings
Electrical stimulation of the terminal induces excitatory postsynaptic potentials (EPSPs) in the neuron and Ca2+ signals in glial processes surrounding the synapse. A similar organization of glial responses to activation of neuronal afferents was also observed in Bergmann glial cells in the cerebellum. It is now well established that these 'glio' transmitters can directly influence the neurons located near the glial cells.
Glial Cells and Nervous System Function
Astrocytes
- Developmental function – producing new neural cells
- Neurogenesis in the adult brain
- Gliogenesis in adult brain
- Developmental function – neuronal guidance
- Regulation of synaptogenesis and control of synaptic maintenance and elimination
- Structural function – creation of the functional microarchitecture of the brain
- Vascular function – creation of glial–vascular interface (blood–brain barrier) and
In primates, including humans, adult neurogenesis is restricted to the hippocampus and subventricular zone. In the cerebellum, granule cells migrate along Bergmann glia, which are derived from radial glia. For example, in the corpus callosum, astrocytes form a bridge (the glial pendulum) that connects the left and right sides of the developing telencephalon.
Regulation of brain microcirculation
Astrocytes themselves are not heavily involved in the function of the blood-brain barrier (which is largely determined by endothelial cells), but astrocytes are important in the regulation of the blood-brain interface as a whole. Interestingly, both effects begin with an increase in endfoot Ca2+ and the release of arachidonic acid (AA). Alternatively, AA can be converted to the vasoconstrictive agent 20 hydroxyeicosatetraenois acid (2-HETE) by a cytochrome 450 enzyme located in the smooth muscle of the arteriole (Figure 7.6).
Ion homeostasis in the extracellular space
- Astrocytes and extracellular potassium homeostasis
- Astrocytes and chloride homeostasis
- Astrocytes and extracellular Ca 2 +
- Astrocytes and regulation of pH
Potassium buffering mediated by Müller cells occurs mainly in the inner plexiform layer of the retina, which contains most of the retinal synapses. Some of the K+ ions may also be released through apical processes, where light causes a decrease in [K+]o in the subretinal space. Some of the K+ ions may also be released through apical processes, where light causes a decrease in [K+]o in the subretinal space.
Regulation of extracellular glutamate concentration
The pH in both the extracellular space and the cytoplasm of neural cells is the subject of tight control by numerous buffer systems. These changes are compensated, at least in part, by bicarbonate and proton transporters present in astroglial cells; of particular importance is the Na+/HCO−3 cotransporter (NBC), which can act in both directions and deliver or remove HCO−3 from the extracellular space. After being accumulated by astrocytes, glutamate is converted to glutamine, and it is this glutamine that is released by the astrocyte into the extracellular space for subsequent uptake into presynaptic neurons – the so-called glutamate-glutamine shuttle (Figure 7.10); Since glutamine is physiologically inactive, its appearance in the extracellular environment is harmless.
Water homeostasis and regulation of the extracellular space volume
- Regulation of water homeostasis
- Redistribution of water following neuronal activity and regulation of the extracellular space
High synaptic activity is associated with a transient decrease in the extracellular space surrounding active synapses. This local contraction of the extracellular space following neuronal activity regulates water transport across astroglial membranes and redistribution of water through the glial syncytium. These events increase the local osmotic pressure at the astrocyte membrane, favoring water uptake through aquaporins; removal of extracellular water results in contraction of the extracellular space.
Neuronal metabolic support
These form the substrate of the astroglial-neuronal lactate shuttle, detailed explanations of which are provided in the text. However, monitoring the distribution of glucose in brain tissue has shown that it is accumulated equally by neurons and astroglial cells. This system depends on glycogen, which is present almost exclusively in astroglial cells in the brain.
Astroglia regulate synaptic transmission
- Morphological plasticity of astroglial synaptic compartment Astrocytes are able to directly influence synaptic transmission in certain brain
Modified from Araque A, Parpura V, Sanzgiri RP Haydon PG (1998) Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons.Eur J Neurosci. During lactation, astrocyte processes shrink, allowing more glutamate into the synaptic cleft, thereby strengthening synaptic transmission. During lactation (which is associated with high levels of oxytocin), astrocytes withdraw their processes from synapses, increasing the effective extracellular glutamate concentration and decreasing glutamate uptake, thereby enhancing glutamatergic transmission (Figure 7.14).
Integration in neuronal–glial networks
Astrocytes as cellular substrate of memory and consciousness?
The most prominent example of such morphological plasticity is observed in the supraoptic nucleus. In white matter, astrocytes can function as presynaptic elements in astroglial-oligodendroglial synapses ( 5 ); Astrocytes and NG2 glia also contact nodes of Ranvier and thus could potentially form synapses with axons at nodes of Ranvier. Astrocytes divide the gray matter space into individual domains, where all neuronal and non-neuronal elements are controlled by a single astroglial cell.
Oligodendrocytes, Schwann Cells and Myelination
The myelin sheath
- Myelin structure
- Composition of myelin
- CNS myelin
- PNS myelin
- Intracellular transport of myelin components
This basic structure of the myelin sheath is the same in the PNS and CNS. This is analogous to the structure of the myelin sheath and the process of myelin compaction. MAG is a member of the immunoglobulin (Ig) gene superfamily with significant homology to neural cell adhesion molecules (NCAM).
Myelination
- Functional development of oligodendrocytes
- Functional development of Schwann cells
- Axon–glial interactions and the control of myelination
FGF-R3 is transiently expressed by premyelinating oligodendrocytes and is important in the initiation of myelination. These cells are multipotent and give rise to both neurons and Schwann cells in the PNS. In the first stage, oligodendrocytes and Schwann cells must recognize axons that require myelination.
Axon ensheathment and establishment of incipient internodal myelin segments: Premyelinating oligodendrocytes that engage axons ready for myeli-
- Myelination in the developing PNS
- Electrical activity and myelination
- Myelin and propagation of the action potential
- Organization of nodes of Ranvier
The longitudinal and radial growth of the myelin sheath directly depends on the diameter of the axons in the unit. Longitudinal growth of the myelin sheath is associated with maturation of paranodal axo-glial junctions and maturation of nodes of Ranvier. Voltage-gated Na+ channels that generate action potential spikes are clustered in the nodal axolemma.
Glia and Nervous System Pathology
General Pathophysiology of Glia
Reactive astrogliosis
Reactive astrocytes in these areas produce chondroitin and keratin, which inhibit axonal regeneration, thus preventing nerve processes from entering the damaged zone. Reactive astrocytes in the areas of isomorphic astrogliosis produce and release various types of growth factors, such as NGF and FGF, and cytokines, such as interleukins. At the same time, reactive astrocytes synthesize numerous recognition molecules (such as extracellular matrix molecules, cell adhesion molecules,.
Wallerian degeneration
Recently, however, it has become apparent that Wallerian degeneration in the PNS is a specialized active process that is not highly dependent on connections with neuronal somata, but rather involves the activation of localized signals in both axons and surrounding glial cells. There is still no complete description of the local signals that initiate and control Wallerian degeneration, but it is clear that an enzyme system known as the ubiquitin-proteasome system (which includes the ubiquitin regulatory enzyme UFD2 and nicotinamide mononucleotide adenylyltransferase) plays a key role. role. Pharmacological inhibition of proteasomes was found to delay Wallerian degeneration in both peripheral and optic nerves.
Activation of microglia
- Pathological potential of activated microglia
Processes of quiescent microglial cells are constantly moving and scanning this territory for possible signals of damage. Moreover, activated microglial cells can show quite heterogeneous properties in different types of pathology and in different parts of the brain. Initial changes in cellular biochemistry occur within minutes of signal presentation, and full activation of microglial cells can follow within hours.
Glia and Diseases of the Nervous System
- Alexander’s disease
- Spreading depression
- Stroke and ischaemia
- Glial cell death during ischaemia
- Astroglia protect the brain against ischaemia
- Astrocytes may exacerbate brain damage upon ischaemia Astrocytes, however, may act not only as protectors of the brain; in certain
- Oligodendrocytes and microglia in stroke
- Cytotoxic brain oedema
- Ischaemic oedema
- Traumatic oedema
- Hepatic encephalopathy
- Hyponatremia
- Neurodegenerative diseases
- Normal ageing
- Post-stroke dementia
- Alzheimer’s disease
- Parkinson’s disease
- Amyotrophic lateral sclerosis
- Neuropathic pain
It is a well-established truth that disruption of blood flow in the brain causes significant damage and death of neuronal cells. The second major pathological role of astrocytes is related to a progression of the infarct core through the penumbra. The spreading wave of depression occurs as often as every 10-15 minutes, which is determined by the refractory period of the cells in the penumbra.
