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Behavior, brain and astrocytes
NEUROL-1807; No. of Pages 4 revue neurologique xxx (2017) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Expert Opinion
Behavior, brain and astrocytes 1.
Introduction
Why is it that the processing of brain activities is considered exclusively in terms of neuronal functioning? Why is the search for new drugs to treat patients with neuropsychiatric disorders based solely on research involving neurons? This seems paradoxical in light of the fact that half of our brain is made up of glial cells and that, during phylogenesis, the density of glial cells is increased compared with that of neurons (1 glial cell vs. 6 neurons in the leech; 1.1 glial cell vs. 1 neuron in humans) [1]? The reason for this paradox can be found in the history of glial cells, which started 160 years ago with their description by Rudolf Virchow as a kind of connective tissue ‘glue’ interspersed between nerve cells [2]. This ‘glue’ was, in fact, composed of cells that looked like stars, and was soon subdivided into fibrous (in white matter) and protoplasmic (gray matter) ‘astrocytes’ [3,4]. Interestingly, several years later, microglia and oligodendrocytes were distinguished from astrocytes [5]. Initially, these glial cells were considered passive elements. However, it was not long before the importance of their physiological role became apparent, as they were involved in: feeding neurons [6]; guiding the migration of neurons during development; maintaining the blood–brain barrier; endocrine properties; and separating nerve fibers to avoid ‘psychic confusion’ [7]. From that time onwards until just recently, the field of glial cells remained relatively dormant. The reason for that intervening silence is likely to be found in the remarkable development of neuronal physiology and the fact that, in contrast to neurons, glial cells do not generate detectable electrical activities and so cannot be recorded. Thus, the aim of this brief review is to show that glial cells are not present in the nervous system simply to fill in the spaces between neurons. Rather, given the pivotal role they play in the production of human behaviors and because their dysfunction contributes to the pathophysiology of several brain disorders, there is good reason to suggest that now is the time to expand our interpretation of pathophysiological neuropsychiatric disorders and how they should be treated. For purposes of simplification, this report concentrates on the role of astrocytes, thereby excluding the contribution of
oligodendrocytes (myelin-forming) and microglia (a form of brain macrophages).
2. Contribution of astrocytes to brain functioning Distributed in the form of a regular polyhedron, each astrocyte is in contact with several hundreds of thousands of synapses. They also have considerable metabolic potential as, in addition to the biochemical parameters characteristic of neurons (such as receptors, neurotransmitters, ion channels), astrocytes produce specific ligands (such as lactate, d-serine) that are characteristic. In brief, astrocytes have essentially three basic selective roles. First, they produce ‘calcium waves’ that propagate slowly from astrocyte to astrocyte over several milimetres via ‘gap junctions’, a sort of tunnel that connects every astrocyte to dozens of others, thereby allowing calcium ions to diffuse from one cellular element to another [8,9]. Second, they participate in the regulation of neuronal activity by releasing neurotransmitters (in particular, glutamate) that act on neurons, making it possible to modulate synaptic activity [10]. Conversely, neurotransmitters released into synapses modulate astrocytic activity. Thus, communication in the central nervous system takes place not only between neurons, but also between neurons and astrocytes within the astrocytic network (the ‘tripartite synapse’) [11]. Finally, astrocytes are able to detect the activity of neurons and to send signals to neighboring capillaries where they are able to pump glucose, the essential nutrient of neurons, which is then taken up by neurons. Within this ‘me´nage a` trois’, astrocytes behave as both ‘feeders’ and ‘garbage collectors’ by eliminating and recycling the chemical compounds produced by neurons. With such a biochemical and cellular background, astrocytes are playing an essential role in at least five main physiological processes essential to proper brain functioning: they control the formation of synapses, first during development to form neural circuits, and then in adulthood to allow the rearrangement of the neuronal network [12]; they guide the migration of neurons during development, allowing them to connect with the target according to a preestablished plan [13];
Please cite this article in press as: Fan X, Agid Y. Behavior, brain and astrocytes. Revue neurologique (2017), http://dx.doi.org/10.1016/ j.neurol.2017.05.017
NEUROL-1807; No. of Pages 4
2
revue neurologique xxx (2017) xxx–xxx
they contribute to neurogenesis during development as well as in adulthood (especially in the hippocampus), participating in various mental functions, such as learning and mood; they participate in the regulation of ion fluxes and functioning of the blood–brain barrier, thereby contributing to the dynamic filter that isolates the brain from the rest of the body [14]; they allow the integration and synchronization of the information conveyed by neurons as a result of a connecting arrangement that forms a continuous cellular network in the three dimensions of space [15].
3.
Role of astrocytes in the control of behaviors
Even today, the dominant theories explaining mental function are ‘neurocentric’. Yet, as astrocytes are so intimately linked to the activities of neurons, it is reasonable to raise questions about their contribution to human behaviors.
3.1.
Astrocytes as an aide-me´moire
According to the reigning theory, memory formation is based on the concept of neuronal plasticity — the rearrangement of synaptic contacts between neurons during learning (longterm potentiation [LTP]). However, it is less well known that memory production may or may not happen depending on the disposition of astrocytes, as shown in the following two examples. First, in a preparation in vitro, if the activity of astrocytes is prevented, the LTP produced (an index of memorization) in neurons is no longer present [16]. This indicates that even though neurons play a role in the process of memory, they cannot do so without the help of astrocytes. Second, the transplantation of astrocytes into the brain of newborn mice appears to improve their memory, provided the preparation originates from human rather than mouse brain astrocytes [17]. If this experiment is confirmed, it suggests that the improvement of memory capacity is not only due to the presence of neurons, but also of astrocytes.
3.2.
Astrocytes as participants in sexual orientation
Transgenic male flies with a mutation involving exclusively astrocytes initiate copulation behavior not only with females — which is normal — but also with males. When the mutation is homozygous, the transgenic males are more likely to seduce males than those with heterozygous mutations, which nevertheless are still more attracted to males [18]. This process suggests that the selective genetic modification of astrocytes is able to influence sexual preferences.
3.3. Astrocytes as modulators of sleep and circadian rhythms Synchronization of neuronal activity during slow-wave sleep appears to be achieved by retraction of astrocytic extensions, causing glutamate diffusion outside of synapses [19]. Genetic manipulation of the expression of an astrocyte-selective enzyme (Ebony) can disrupt circadian rhythm, as demonstrated in flies [20]. These experiments suggest that astrocytes
can modulate the neuronal circuitry involved in sleep physiology and circadian behaviors.
4.
Role of astrocytes in neurological disorders
Given the permanent exchange between neurons and astrocytes, all disorders of the nervous system thought to exclusively affect neurons should also implicate astrocyte dysfunction. In fact, neuronal death is always accompanied by either astrocyte accumulation (gliosis) or an anomaly of their functioning, or both. However, whether these astrocytes are protective or deleterious is open to question. Several experiments with cell cultures show that the alteration of astrocytes can contribute to neuronal dysfunction, resulting in conditions such as trisomy 21, Rett syndrome and fragile X syndrome. In fact, when astrocytes with the mutation characteristic of each of these disorders are introduced among healthy neurons in a suitable culture medium, the neurons fail to develop normally [12]. This suggests that a developmental abnormality of astrocytes can play a role in the mechanisms underlying neurodevelopmental disorders. What then is the role of astrocytes in the appearance of other major neurological disorders? Alexander disease is a rare genetic disorder that, from birth, results in macrocephaly, epileptic seizures, intellectual retardation and, eventually, premature death. The cause is a mutation in the gene for a protein characteristic of astrocytes — glial fibrillary acidic protein (GFAP) — that, by accumulating in astrocytes, causes their hypertrophy [21]. When seeking evidence that glial dysfunction can cause behavioral chaos, Alexander disease is a striking example. The involvement of astrocytes in neuronal death is also well illustrated in neurodegenerative disorders such as amyotrophic lateral sclerosis and cerebellar ataxia [22,23]. In Alzheimer’s disease (AD), there are two reasons to involve astrocyte dysfunction in the pathological mechanism. First, in AD, neuronal loss is accompanied by the accumulation of amyloid-beta protein within senile plaques, but always in the presence of vast amounts of astrocytes. According to the current theory, astrocytes, which are known to capture and degrade this protein, are overwhelmed by its accumulation [24], causing them to lose their ability to provide metabolic support to neurons, thus leading to neuronal death. This type of observation demonstrates that the role of astrocytes in the pathophysiology of AD cannot be dismissed. Also, when people carry a particular form of apolipoprotein E — namely, ApoE4 — they are eight times more likely to develop the disease than those carrying another form of the molecule. The fact that ApoE4 is exclusively produced in astrocytes shows that they participate in the development of AD. Another type of dementia, frontotemporal dementia, is characterized by the inappropriate accumulation of tau proteins in the brain. When the tau mutation is selectively introduced into astrocytes of transgenic mice (resulting in the overexpression of tau proteins in astrocytes, but not in neurons), neuronal loss is observed in the brain, with a concomitant decrease in cognitive capacity in the mutated mice [25]. This type of experiment shows that pathological astrocytes can cause neuronal dysfunction, leading to neurodegeneration.
Please cite this article in press as: Fan X, Agid Y. Behavior, brain and astrocytes. Revue neurologique (2017), http://dx.doi.org/10.1016/ j.neurol.2017.05.017
NEUROL-1807; No. of Pages 4 revue neurologique xxx (2017) xxx–xxx
In Parkinson’s disease (PD), the more dopaminergic neurons destroyed in the substantia nigra, the more astrocytes accumulate. Such accumulation of astrocytes is greatest in the most damaged, internal part of the substantia nigra—but not in the external part, which is spared by the pathological process—as if the astrocytes are there to limit neuronal loss. This potentially protective role of astrocytes in reducing the vulnerability of dopaminergic neurons is confirmed when examining the substantia nigra in non-PD subjects, in whom the density of astrocytes is six times greater in the median midbrain, which contains dopaminergic neurons known to be unaffected, whereas the concentration of astrocytes is low in parts of the substantia nigra known to degenerate in parkinsonian patients [26]. Again, it is as if the astrocytes are present to protect dopaminergic neurons against degeneration. In patients with epilepsy, the initiation of seizures in cortical neurons is accompanied by significant gliosis. A classic example, observed in patients with temporal epilepsy, is ‘hippocampal sclerosis’, characterized by altered astrocyte foci. When an epileptic discharge is produced in hippocampal slice cultures, the induced epileptic discharge can surprisingly persist in the absence of neuronal activity (by tetrodotoxin blockade). Moreover, the epileptic discharges can arise in neighboring astrocytes, and are suppressed by antiepileptic drugs acting directly on astrocytes [27]. Thus, at least some forms of epilepsy result from the dysfunction of astrocytes, which therefore represent a potential target for the development of new antiepileptic drugs. In patients with spinal cord injury, millions of axons are separated from their extensions by a solution of continuity. The glial scar (gliosis) then forms a fibrous barrier through the accumulation of reactive astrocytes [21]. Not only does the presence of these supernumerary astrocytes prevent the regeneration of neurons, but it also leads to the formation of deleterious aberrant synapses and secretion of substances toxic to neurons [23]. This surely is a therapeutic dimension to take into consideration. Neuroprotective treatments of cerebral infarction, which invariably target neurons, have so far failed. Neurons are the first to suffer, but other phenomena also intervene: alternating vasoconstriction and vasodilation of vessels; breach of the blood-brain barrier; spread of edema; and accumulation and activation of astrocytes. The role of astrocytes is ambiguous, however: it is deleterious by the secretion of free radicals and cytokines, inflammatory reactions and release of an excess of glutamate, but also protective via the secretion of, for example, trophic factors and erythropoietin [28]. It is not unreasonable to predict that future therapeutics will aim to ensure the survival and proper functioning not only of neurons, but also of astrocytes. The final example is hepatic encephalopathy. Coma is caused by cerebral edema, leading to an increase of intracranial pressure. This edema results essentially from the swelling of astrocytes in response to an excess of ammonium (NH4), produced by the diseased liver. When this protective mechanism becomes swamped, the NH4 taken up by astrocytes turns into glutamine, which then accumulates in the astrocytes, leading to the formation of toxic edema [29]. In this case, the astrocytes are initially protective by absorbing
3
ammonium, but then become deleterious when this uptake goes beyond a certain threshold, thereby exceeding the compensatory mechanism. In short, given the close relationship between neurons and astrocytes, it seems ill advised to concentrate on saving neurons while at the same time ignoring astrocytes. Indeed, it is perhaps because this dimension of pathology has not been sufficiently taken into account that thousands of therapeutic trials to manage patients with brain disorders have failed in recent years. Thus, it is time to design new drugs that not only act on neurons but also on glial cells, including astrocytes.
5.
Conclusion
How could it be possible to envisage the role of the brain in the control of human behaviors while neglecting half of it? What would have happened had it been possible to record the electrical activity of astrocytes instead of neurons at the beginning of the last century? It is likely that a model of brain processing based exclusively on the physiology of glial cells would have been created. As briefly summarized in this review, the normal functioning of astrocytes appears to be a necessary condition, albeit insufficient on its own, for the control of human behavior. Thus, it is perhaps time to conceive a behavioral physiology based not only on neurons, but also involving astrocytes. Neurologists should also take into account the concept of a ‘me´nage a` trois’ that includes neurons, astrocytes and capillaries to provide modern pathophysiological interpretations of neuropsychiatric disorders. In addition, our partners in the pharmaceutical industry would perhaps also do well to identify drugs that act on neurons or astrocytes, or even both.
Disclosure of interest The authors declare that they have no competing interest.
references
[1] Herculano-Houzel S. The human brain in numbers: a linearly scaled-up primate brain. Front Hum Neurosci 2009;9:31. [2] Somjen GG. Nervenkitt notes on the history of the concept of neuroglia. Glia 1988;1:2–9. [3] Deiters O. Untersuchungen u¨ber Gehirn und Ru¨ckenmark des Menschen und der Sa¨ugethiere. Braunschweig: Vieweg; 1865. [4] Andriezen WL. The neuroglia elements of the brain. Br Med J 1893;2:227–30. [5] del Rı´o-Hortega P. Glı´a con pocas prolongaciones (oligodendroglia). Bol Soc Esp Biol 1921;XXI:1–43. [6] Golgi C. Sulla fina anatomia della sistema nervosa. In: Opera Omnia, editor. Riv. Sper. Freniatr. 1885-1886., 16. Milano: U. Hoepfli; 1903. [7] Cajal. Histologie du syste`me nerveux de l’homme et des verte´bre´s. Paris: Maloine; 1909. [8] Charles AC. Glia-neuron intercellular calcium signalling. Dev Neurosci 1994;16:196–206.
Please cite this article in press as: Fan X, Agid Y. Behavior, brain and astrocytes. Revue neurologique (2017), http://dx.doi.org/10.1016/ j.neurol.2017.05.017
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[9] Brightman MW, Reese TS. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 1969;40:648–77. [10] Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG. Glutamate-mediated astrocyte-neuron signalling. Nature 1994;369:744–7. [11] Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 1999;22:208–15. [12] Clarke LE, Barres BA. Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 2013;14:311–21. [13] Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 2003;26:523–30. [14] De Pitta` M, Brunel N, Volterra A, Astrocytes:. Orchestrating synaptic plasticity? Neuroscience 2016;323:43–61. [15] Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 2005;6:626–40. [16] Henneberger C, Papouin T, Oliet SH, Rusakov DA. Longterm potentiation depends on release of d-serine from astrocytes. Nature 2010;463:232–6. [17] Han X, Chen M, Wang F, et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 2013;12:342–53. [18] Grosjean Y, Grillet M, Augustin H, Ferveur JF, Featherstone DE. A glial amino-acid transporter controls synapse strength and courtship in drosophila. Nat Neurosci 2008;11:54–61. [19] Bellesi M, de Vivo L, Tononi G, Cirelli C. Effects of sleep and wake on astrocytes: clues from molecular and ultrastructural studies. BMC Biol 2015;13:66. [20] Emery P, Freeman MR. Glia got rhythm. Neuron 2007;55:337–9. [21] Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol 2010;119:7–35. [22] Seifert G, Schilling K, Steinha¨user C. Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 2006;7:194–206.
[23] Lobsiger CS, Cleveland DW. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci 2007;10:1355–60. [24] Allaman I, Gavillet M, Be´langer M, et al. Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci 2010;30:3326–38. [25] Forman MS, Lal D, Zhang B, et al. Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. J Neurosci 2005;25(14):3539–50. [26] Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F. Glutathione peroxidase, glial cells and parkinson’s disease. Neuroscience 1993;52:1–6. [27] Tian GF, Azmi H, Takano T, et al. An astrocytic basis of epilepsy. Nat Med 2005;11:973–81. [28] Zhao Y, Rempe DA. Targeting astrocytes for stroke therapy. Neurotherapeutics 2010;7:439–51. [29] Lizardi-Cervera J, Almeda P, Guevara L, Uribe M. Hepatic encephalopathy: a review. Ann Hepatol 2003;2:122–30.
X. Fan* Y. Agid Institut du cerveau et de la moelle e´pinie`re, ICM, UPMC universite´ Paris-06, hoˆpital de la Pitie´-Salpeˆtrie`re, AP-HP, 47, boulevard de l’Hoˆpital, 75013 Paris, France *Corresponding author. E-mail address: [email protected] (X. Fan) Received 19 February 2017 Received in revised form 8 April 2017 Accepted 17 April 2017 Available online xxx http://dx.doi.org/10.1016/j.neurol.2017.05.017 0035-3787/# 2017 Elsevier Masson SAS. Tous droits re´serve´s.
Please cite this article in press as: Fan X, Agid Y. Behavior, brain and astrocytes. Revue neurologique (2017), http://dx.doi.org/10.1016/ j.neurol.2017.05.017
Available online at
ScienceDirect www.sciencedirect.com
Expert Opinion
Behavior, brain and astrocytes 1.
Introduction
Why is it that the processing of brain activities is considered exclusively in terms of neuronal functioning? Why is the search for new drugs to treat patients with neuropsychiatric disorders based solely on research involving neurons? This seems paradoxical in light of the fact that half of our brain is made up of glial cells and that, during phylogenesis, the density of glial cells is increased compared with that of neurons (1 glial cell vs. 6 neurons in the leech; 1.1 glial cell vs. 1 neuron in humans) [1]? The reason for this paradox can be found in the history of glial cells, which started 160 years ago with their description by Rudolf Virchow as a kind of connective tissue ‘glue’ interspersed between nerve cells [2]. This ‘glue’ was, in fact, composed of cells that looked like stars, and was soon subdivided into fibrous (in white matter) and protoplasmic (gray matter) ‘astrocytes’ [3,4]. Interestingly, several years later, microglia and oligodendrocytes were distinguished from astrocytes [5]. Initially, these glial cells were considered passive elements. However, it was not long before the importance of their physiological role became apparent, as they were involved in: feeding neurons [6]; guiding the migration of neurons during development; maintaining the blood–brain barrier; endocrine properties; and separating nerve fibers to avoid ‘psychic confusion’ [7]. From that time onwards until just recently, the field of glial cells remained relatively dormant. The reason for that intervening silence is likely to be found in the remarkable development of neuronal physiology and the fact that, in contrast to neurons, glial cells do not generate detectable electrical activities and so cannot be recorded. Thus, the aim of this brief review is to show that glial cells are not present in the nervous system simply to fill in the spaces between neurons. Rather, given the pivotal role they play in the production of human behaviors and because their dysfunction contributes to the pathophysiology of several brain disorders, there is good reason to suggest that now is the time to expand our interpretation of pathophysiological neuropsychiatric disorders and how they should be treated. For purposes of simplification, this report concentrates on the role of astrocytes, thereby excluding the contribution of
oligodendrocytes (myelin-forming) and microglia (a form of brain macrophages).
2. Contribution of astrocytes to brain functioning Distributed in the form of a regular polyhedron, each astrocyte is in contact with several hundreds of thousands of synapses. They also have considerable metabolic potential as, in addition to the biochemical parameters characteristic of neurons (such as receptors, neurotransmitters, ion channels), astrocytes produce specific ligands (such as lactate, d-serine) that are characteristic. In brief, astrocytes have essentially three basic selective roles. First, they produce ‘calcium waves’ that propagate slowly from astrocyte to astrocyte over several milimetres via ‘gap junctions’, a sort of tunnel that connects every astrocyte to dozens of others, thereby allowing calcium ions to diffuse from one cellular element to another [8,9]. Second, they participate in the regulation of neuronal activity by releasing neurotransmitters (in particular, glutamate) that act on neurons, making it possible to modulate synaptic activity [10]. Conversely, neurotransmitters released into synapses modulate astrocytic activity. Thus, communication in the central nervous system takes place not only between neurons, but also between neurons and astrocytes within the astrocytic network (the ‘tripartite synapse’) [11]. Finally, astrocytes are able to detect the activity of neurons and to send signals to neighboring capillaries where they are able to pump glucose, the essential nutrient of neurons, which is then taken up by neurons. Within this ‘me´nage a` trois’, astrocytes behave as both ‘feeders’ and ‘garbage collectors’ by eliminating and recycling the chemical compounds produced by neurons. With such a biochemical and cellular background, astrocytes are playing an essential role in at least five main physiological processes essential to proper brain functioning: they control the formation of synapses, first during development to form neural circuits, and then in adulthood to allow the rearrangement of the neuronal network [12]; they guide the migration of neurons during development, allowing them to connect with the target according to a preestablished plan [13];
Please cite this article in press as: Fan X, Agid Y. Behavior, brain and astrocytes. Revue neurologique (2017), http://dx.doi.org/10.1016/ j.neurol.2017.05.017
NEUROL-1807; No. of Pages 4
2
revue neurologique xxx (2017) xxx–xxx
they contribute to neurogenesis during development as well as in adulthood (especially in the hippocampus), participating in various mental functions, such as learning and mood; they participate in the regulation of ion fluxes and functioning of the blood–brain barrier, thereby contributing to the dynamic filter that isolates the brain from the rest of the body [14]; they allow the integration and synchronization of the information conveyed by neurons as a result of a connecting arrangement that forms a continuous cellular network in the three dimensions of space [15].
3.
Role of astrocytes in the control of behaviors
Even today, the dominant theories explaining mental function are ‘neurocentric’. Yet, as astrocytes are so intimately linked to the activities of neurons, it is reasonable to raise questions about their contribution to human behaviors.
3.1.
Astrocytes as an aide-me´moire
According to the reigning theory, memory formation is based on the concept of neuronal plasticity — the rearrangement of synaptic contacts between neurons during learning (longterm potentiation [LTP]). However, it is less well known that memory production may or may not happen depending on the disposition of astrocytes, as shown in the following two examples. First, in a preparation in vitro, if the activity of astrocytes is prevented, the LTP produced (an index of memorization) in neurons is no longer present [16]. This indicates that even though neurons play a role in the process of memory, they cannot do so without the help of astrocytes. Second, the transplantation of astrocytes into the brain of newborn mice appears to improve their memory, provided the preparation originates from human rather than mouse brain astrocytes [17]. If this experiment is confirmed, it suggests that the improvement of memory capacity is not only due to the presence of neurons, but also of astrocytes.
3.2.
Astrocytes as participants in sexual orientation
Transgenic male flies with a mutation involving exclusively astrocytes initiate copulation behavior not only with females — which is normal — but also with males. When the mutation is homozygous, the transgenic males are more likely to seduce males than those with heterozygous mutations, which nevertheless are still more attracted to males [18]. This process suggests that the selective genetic modification of astrocytes is able to influence sexual preferences.
3.3. Astrocytes as modulators of sleep and circadian rhythms Synchronization of neuronal activity during slow-wave sleep appears to be achieved by retraction of astrocytic extensions, causing glutamate diffusion outside of synapses [19]. Genetic manipulation of the expression of an astrocyte-selective enzyme (Ebony) can disrupt circadian rhythm, as demonstrated in flies [20]. These experiments suggest that astrocytes
can modulate the neuronal circuitry involved in sleep physiology and circadian behaviors.
4.
Role of astrocytes in neurological disorders
Given the permanent exchange between neurons and astrocytes, all disorders of the nervous system thought to exclusively affect neurons should also implicate astrocyte dysfunction. In fact, neuronal death is always accompanied by either astrocyte accumulation (gliosis) or an anomaly of their functioning, or both. However, whether these astrocytes are protective or deleterious is open to question. Several experiments with cell cultures show that the alteration of astrocytes can contribute to neuronal dysfunction, resulting in conditions such as trisomy 21, Rett syndrome and fragile X syndrome. In fact, when astrocytes with the mutation characteristic of each of these disorders are introduced among healthy neurons in a suitable culture medium, the neurons fail to develop normally [12]. This suggests that a developmental abnormality of astrocytes can play a role in the mechanisms underlying neurodevelopmental disorders. What then is the role of astrocytes in the appearance of other major neurological disorders? Alexander disease is a rare genetic disorder that, from birth, results in macrocephaly, epileptic seizures, intellectual retardation and, eventually, premature death. The cause is a mutation in the gene for a protein characteristic of astrocytes — glial fibrillary acidic protein (GFAP) — that, by accumulating in astrocytes, causes their hypertrophy [21]. When seeking evidence that glial dysfunction can cause behavioral chaos, Alexander disease is a striking example. The involvement of astrocytes in neuronal death is also well illustrated in neurodegenerative disorders such as amyotrophic lateral sclerosis and cerebellar ataxia [22,23]. In Alzheimer’s disease (AD), there are two reasons to involve astrocyte dysfunction in the pathological mechanism. First, in AD, neuronal loss is accompanied by the accumulation of amyloid-beta protein within senile plaques, but always in the presence of vast amounts of astrocytes. According to the current theory, astrocytes, which are known to capture and degrade this protein, are overwhelmed by its accumulation [24], causing them to lose their ability to provide metabolic support to neurons, thus leading to neuronal death. This type of observation demonstrates that the role of astrocytes in the pathophysiology of AD cannot be dismissed. Also, when people carry a particular form of apolipoprotein E — namely, ApoE4 — they are eight times more likely to develop the disease than those carrying another form of the molecule. The fact that ApoE4 is exclusively produced in astrocytes shows that they participate in the development of AD. Another type of dementia, frontotemporal dementia, is characterized by the inappropriate accumulation of tau proteins in the brain. When the tau mutation is selectively introduced into astrocytes of transgenic mice (resulting in the overexpression of tau proteins in astrocytes, but not in neurons), neuronal loss is observed in the brain, with a concomitant decrease in cognitive capacity in the mutated mice [25]. This type of experiment shows that pathological astrocytes can cause neuronal dysfunction, leading to neurodegeneration.
Please cite this article in press as: Fan X, Agid Y. Behavior, brain and astrocytes. Revue neurologique (2017), http://dx.doi.org/10.1016/ j.neurol.2017.05.017
NEUROL-1807; No. of Pages 4 revue neurologique xxx (2017) xxx–xxx
In Parkinson’s disease (PD), the more dopaminergic neurons destroyed in the substantia nigra, the more astrocytes accumulate. Such accumulation of astrocytes is greatest in the most damaged, internal part of the substantia nigra—but not in the external part, which is spared by the pathological process—as if the astrocytes are there to limit neuronal loss. This potentially protective role of astrocytes in reducing the vulnerability of dopaminergic neurons is confirmed when examining the substantia nigra in non-PD subjects, in whom the density of astrocytes is six times greater in the median midbrain, which contains dopaminergic neurons known to be unaffected, whereas the concentration of astrocytes is low in parts of the substantia nigra known to degenerate in parkinsonian patients [26]. Again, it is as if the astrocytes are present to protect dopaminergic neurons against degeneration. In patients with epilepsy, the initiation of seizures in cortical neurons is accompanied by significant gliosis. A classic example, observed in patients with temporal epilepsy, is ‘hippocampal sclerosis’, characterized by altered astrocyte foci. When an epileptic discharge is produced in hippocampal slice cultures, the induced epileptic discharge can surprisingly persist in the absence of neuronal activity (by tetrodotoxin blockade). Moreover, the epileptic discharges can arise in neighboring astrocytes, and are suppressed by antiepileptic drugs acting directly on astrocytes [27]. Thus, at least some forms of epilepsy result from the dysfunction of astrocytes, which therefore represent a potential target for the development of new antiepileptic drugs. In patients with spinal cord injury, millions of axons are separated from their extensions by a solution of continuity. The glial scar (gliosis) then forms a fibrous barrier through the accumulation of reactive astrocytes [21]. Not only does the presence of these supernumerary astrocytes prevent the regeneration of neurons, but it also leads to the formation of deleterious aberrant synapses and secretion of substances toxic to neurons [23]. This surely is a therapeutic dimension to take into consideration. Neuroprotective treatments of cerebral infarction, which invariably target neurons, have so far failed. Neurons are the first to suffer, but other phenomena also intervene: alternating vasoconstriction and vasodilation of vessels; breach of the blood-brain barrier; spread of edema; and accumulation and activation of astrocytes. The role of astrocytes is ambiguous, however: it is deleterious by the secretion of free radicals and cytokines, inflammatory reactions and release of an excess of glutamate, but also protective via the secretion of, for example, trophic factors and erythropoietin [28]. It is not unreasonable to predict that future therapeutics will aim to ensure the survival and proper functioning not only of neurons, but also of astrocytes. The final example is hepatic encephalopathy. Coma is caused by cerebral edema, leading to an increase of intracranial pressure. This edema results essentially from the swelling of astrocytes in response to an excess of ammonium (NH4), produced by the diseased liver. When this protective mechanism becomes swamped, the NH4 taken up by astrocytes turns into glutamine, which then accumulates in the astrocytes, leading to the formation of toxic edema [29]. In this case, the astrocytes are initially protective by absorbing
3
ammonium, but then become deleterious when this uptake goes beyond a certain threshold, thereby exceeding the compensatory mechanism. In short, given the close relationship between neurons and astrocytes, it seems ill advised to concentrate on saving neurons while at the same time ignoring astrocytes. Indeed, it is perhaps because this dimension of pathology has not been sufficiently taken into account that thousands of therapeutic trials to manage patients with brain disorders have failed in recent years. Thus, it is time to design new drugs that not only act on neurons but also on glial cells, including astrocytes.
5.
Conclusion
How could it be possible to envisage the role of the brain in the control of human behaviors while neglecting half of it? What would have happened had it been possible to record the electrical activity of astrocytes instead of neurons at the beginning of the last century? It is likely that a model of brain processing based exclusively on the physiology of glial cells would have been created. As briefly summarized in this review, the normal functioning of astrocytes appears to be a necessary condition, albeit insufficient on its own, for the control of human behavior. Thus, it is perhaps time to conceive a behavioral physiology based not only on neurons, but also involving astrocytes. Neurologists should also take into account the concept of a ‘me´nage a` trois’ that includes neurons, astrocytes and capillaries to provide modern pathophysiological interpretations of neuropsychiatric disorders. In addition, our partners in the pharmaceutical industry would perhaps also do well to identify drugs that act on neurons or astrocytes, or even both.
Disclosure of interest The authors declare that they have no competing interest.
references
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X. Fan* Y. Agid Institut du cerveau et de la moelle e´pinie`re, ICM, UPMC universite´ Paris-06, hoˆpital de la Pitie´-Salpeˆtrie`re, AP-HP, 47, boulevard de l’Hoˆpital, 75013 Paris, France *Corresponding author. E-mail address: [email protected] (X. Fan) Received 19 February 2017 Received in revised form 8 April 2017 Accepted 17 April 2017 Available online xxx http://dx.doi.org/10.1016/j.neurol.2017.05.017 0035-3787/# 2017 Elsevier Masson SAS. Tous droits re´serve´s.
Please cite this article in press as: Fan X, Agid Y. Behavior, brain and astrocytes. Revue neurologique (2017), http://dx.doi.org/10.1016/ j.neurol.2017.05.017