REVIEWAntidepressants act directly on astrocytes: Evidences and functional consequences
Introduction
Despite the existing effective treatment strategies, the prevalence of depressive spectrum disorders is increasing worldwide. This growing burden calls for a better understanding of the pathophysiology of mood disorders and of the real therapeutic action of antidepressants. Already a decade ago, a theory has been put forward that suggested that abnormal functioning of glial cells could contribute to the pathophysiology of mood disorders (Coyle and Schwarcz, 2000, Cotter et al., 2001, Rajkowska and Miguel-Hidalgo, 2007). This theory was based on the numerous observations originating from post-mortem histopathological studies that reported on reduced glial cell numbers in various frontolimbic areas of depressed patients, including the prefrontal and medial prefrontal cortex, the dorsolateral and orbitofrontal cortex, the amygdala and the hippocampus as well (for reviews see: Cotter et al., 2001, Harrison, 2002, Rajkowska and Miguel-Hidalgo, 2007, Drevets et al., 2008, Hercher et al., 2009).
During the last decade, our understanding on the various forms of astrocytic functions increased at a faster rate than for any other cell type in the nervous system, still astrocytes have often been neglected in the field of psychopharmacology. Our aim with this review was to gather the scattered, but abundant experimental evidences on the fact that antidepressant therapies do act on astrocytes, modify their function and morphology. We argue here, that the understanding of astrocytic involvement in antidepressant actions could help us to identify novel targets for the development of antidepressant drugs. We will focus mainly on astrocytes, but we will occasionally mention relevant data on other glial cell types, i.e. on oligodendrocytes, NG2-positive cells and microglia.
Historically, astrocytes have been viewed as a homogeneous population of cells, providing passive support for the neurons and carrying out numerous housekeeping functions, including energy supply and removal of toxic metabolites. This view has dramatically changed after numerous unexpected findings. However, our knowledge on astrocytic functions is still incomplete.
Astrocytes are considered the most numerous cell type in the mammalian brain (Sofroniew and Vinters, 2010). According to the general assumption, the human brain consists of 10–100 billion neurons and because glial cells are believed to outnumber neurons by 10–50 times, thus, astrocytes should be the most abundant cell type in the brain, probably making up almost one half of the entire cell population in the adult brain (Kandel, 2000, Rajkowska and Miguel-Hidalgo, 2007, Kimelberg and Nedergaard, 2010). Recent experimental data based on stereological cell counting – the gold standard for cell quantification – however report on much lower astrocyte (and glial cell) numbers. A study by Pelvig et al. (2008) quantified the number of neurons and various types of glial cells in the neocortex of adult humans, and reported the following numbers: the total number of glial cells were 27.9 billion in females and 38.9 billion in males, whereas the total number of neocortical neurons were 21.4 billion in females and 26.3 billion in males, providing a glia/neuron ratio of 1.3 for females and 1.5 for males. Furthermore, they documented the following distribution of the three main types of glial cells in the human neocortex: 75% oligodendrocytes, 20% astrocytes and 5% of microglial cells (Pelvig et al., 2008). Based on these data one can conclude that the total number of astrocytes in the four lobes of the adult human neocortex is ranging between 4.8 billion (in females) and 7.8 billion (in males). This also indicates that astrocytes make up only about 10% of the total cell number (neuron+glia) in the adult human neocortex.
The exact identification and classification of astrocytes is also a controversial issue since these cells might be as heterogeneous in physiology and form as neurons (Kimelberg, 2004, Kimelberg, 2010, Barres, 2008, Cahoy et al., 2008, Hewett, 2009, Matyash and Kettenmann, 2010). The traditional classification was based on the morphology and location of these cells and grouped them into two main categories, the protoplasmic and the fibrillary (or fibrous) astrocytes (Miller and Raff, 1984). Protoplasmic astrocytes are found in the gray matter and their processes ensheath synapses as well as blood vessels while the fibrillary astrocytes are located to the white matter where they contact nodes of Ranvier and blood vessels (Hewett, 2009, Sofroniew and Vinters, 2010). There are other, more specialized astrocytes, like the Müller glia of the retina and Bergmann glia in the cerebellum and some suggests that certain types of astrocytes might be unique and specific to the human and primate neocortex (Oberheim et al., 2009).
Another classification approach is based on the antigenic phenotype of these cells and relies largely on the most commonly used astrocytic markers like GFAP, S100B, Aquaporin 4, GLAST or GLT-1 (Hewett, 2009). This classification has its own limits as many of these commonly used astrocytic markers are either not uniformly expressed in all astrocytes, or do not label completely the cell body and all the processes. For example, GFAP, the best known astrocytic marker is preferentially expressed in white matter over gray matter astrocytes and does not label all the processes (Bushong et al., 2002). Aquaporin 4 is a highly astrocyte specific marker, but it is localized only to the endfeet of the cells. Another problem with these astrocytic markers is their specificity: for example, GFAP is also expressed by stem cells in the adult brain, but these cell types are normally not considered as astrocytes (Hewett, 2009, Robel et al., 2011). The other most widely used marker S100B labels both the gray and white matter astrocytes, but it also labels oligodendrocyte progenitor cells and premyelinating, postmitotic oligodendrocytes.
Recent methodical advances greatly increased our knowledge about the identity, structure and organization of astrocytes. Microinjection of fluorescent dyes into single hippocampal astrocytes revealed a highly ordered arrangement of these cells, with each astrocyte covering its own specific territory that interfaces with the microvasculature and enveloping possibly thousands of synapses (Bushong et al., 2002). Genetic engineering enables us to generate transgenic mice in which astrocytes are labeled by fluorescent proteins that are expressed under the control of various astrocyte specific promoters (e.g. Zhuo et al., 1997, Nolte et al., 2001, Zuo et al., 2004, Slezak et al., 2007). This approach even allows the non-invasive in situ analysis of astrocytes under physiological and pathological conditions (Zhu et al., 2004, Cordeau et al., 2008). Another significant methodical progress is the production of transcriptome databases for astrocytes, which on one hand revealed surprising molecular diversity among astrocytes and on the other hand brought to light numerous new cell-specific markers e.g. the aldehyde dehydrogenase 1 family, member L1 (Aldh1L1) gene (Bachoo et al., 2004, Lovatt et al., 2007, Cahoy et al., 2008, Roesch et al., 2008). Furthermore, it is expected that the use of optogenetic tools will revolutionize our knowledge on astrocytic functions (Figueiredo et al., 2011).
Traditionally astrocytes have been considered to be passive, non-excitable support cells that provide scaffold to neurons. This view has changed dramatically since the discoveries that these cells express voltage-gated channels and various neurotransmitter receptors. Today, astrocytes are viewed as “excitable” cells that are activated by internal and external signals upon which they – most probably – release “gliotransmitters” affecting synaptic communication (Volterra and Meldolesi, 2005, Hamilton and Attwell, 2010, Kimelberg, 2010). Additionally, astrocytic processes wrap around synaptic connections and by that they not only insulate them, but actively modulate synaptic transmission as a third party member of the so called “tripartite synapse” (Haydon, 2001, Perea et al., 2009). Astrocytes also exert significant control over synapse formation, adult neurogenesis and vascular tone (Horner and Palmer, 2003, Attwell et al., 2010, Eroglu and Barres, 2010, Kimelberg, 2010).
Section snippets
Experimental evidences that antidepressant therapies act on astrocytes
The first antidepressant drugs were discovered in the late 1950s by serendipity, when two unrelated compounds were found to improve the mood of treated patients. One of them was developed to treat tuberculosis (iproniazid, a monoamine oxidase inhibitor) and the other was imipramine, originally developed to be an antipsychotic compound with anti-histaminic properties. These compounds were later shown to exert their antidepressant effects through enhancement of synaptic serotonin and
The functional consequences of antidepressant action on astrocytes
In the second part of this review we will summarize astrocytic functions that were on one hand implicated in the pathophysiology of depression and on the other hand are likely to be modulated by the currently available antidepressant interventions. We will also propose some theories to explain the potential role of astrocytes in antidepressant action.
Summary
The primary aim of the present review was to put together all the currently available and relevant experimental findings on the evidence that antidepressant therapies act directly on astrocytes. Antidepressants, as any drug that is able to pass the blood–brain barrier, when doing so they come in direct contact with astrocytes. As we demonstrated, there is a large amount of convincing evidence indicating that antidepressant treatments affect diverse astrocytic functions such as the regulation of
Role of the funding source
This study was institutionally supported.
Contributors
Both authors contributed to the literature searches and analyses. Both authors contributed to the writing of the paper and both have approved the final version of the manuscript.
Conflict of interest
No conflict of interest or financial support is present for the authors.
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2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :However, more recently, it has become evident that the abnormal function of glial cells might also be implicated in such disorders. In fact, these cells enhance several brain functions and contribute to the pathophysiology of depression (Czeh and Di Benedetto, 2013). Therefore, glial cells are nowadays considered crucial elements in brain circuitry.