Τετάρτη, 11 Οκτωβρίου 2017

Link of Astrocytes to Depression

Despite the neurocentric approach of the field, a link between astrocytes and depression has been currently established, through direct and indirect evidence.
It was long acknowledged that astrocytes influence mental health indirectly: they have homeostatic functions that maintain a ‘friendly’ environment for the cells, and they protect the brain from unwanted intruders through the blood- brain barrier (Abbott, Hansson, Ronnback, 2006). Thus they act as assistants to neurons- therefore play an indirect role in mental disorders.
New evidence has revealed more functions of the astrocytes themselves: they are active in information processing of the brain. It has been discovered that astrocytes can communicate with neurons; many synapses (not all) are tripartite, thus composed by the pre- synaptic and post- synaptic terminals, and some underlying astrocytic foot processes, which strengthening the synapses, fact which makes astrocytes active elements in the information processing occurring in the brain (Araque, Navarrete, Perea, 2009). Not only do astrocytes play a central role in the production and release of glutamate, but they also modulate overall neurotransmitter release through certain properties they have, that allow them to regulate and specify the process of NT release (Bergersen et al, 2007). Moreover, they are important components in adult hippocampal neurogenesis: they interfere with the molecular control of the process. Specifically, they secrete WNT protein, which has the ability to give rise to neuronal cells, thus it modulates neurogenesis (Aimone, Deng, Gage, 2010).
Moreover, it has been discovered that astrocytes communicate with each other, forming complex networks. Those networks are linked with gap junctions, which elicit, not electrical stimulation, but CA++. The molecular parts of these junctions are certain proteins, the connexins, plenty of which have been identified. The increase of CA++ can trigger an increased release of neurotransmitters between the linked cells and can cause them to be fired in rhythmic patterns (Giaume, Holcman Koulakoff, Rouach, Roux, 2010).
All these functions of astrocytes have been particularly linked with depression- a connection established through animal experiments, post- mortem studies and through investigating further the effects of current antidepressants.
Animal studies, mainly with mice, have revealed that blocking of the gap junctions can have negative effects on the behaviour of the animal, such as depressive symptoms. This could mean that a dysfunction in networks is enough on its own to lead to depressive behaviors. Moreover, in animal models of depression a reduction in AHN has been shown, process involving astrocytes, as previously mentioned. This effect can be reversed/ reduced with antidepressants, which promote AHN (Aimone, Deng, Gage, 2010). At the same time, it has been shown that mice that have experienced chronic unpredicted stress, which is their own model of depression, were lead to dysfunction of astrocytes and their networks in the prefrontal cortex. Interestingly, this effect was reduced with the administration of antidepressants, specifically riluzole (yet other studies have focused on different drugs) (Banasr et al, 2010).
Post- mortem studies in individuals who committed suicide revealed that they had lower levels of the connecting proteins used by astrocytic networks, such as Cx43 or GFAP, compared to healthy controls (Mechawar, Nagy, Torres- Platas, Turecki, 2016). Other studies have shown that individuals who have committed suicide or those who suffer from depression have a reduced amount of astrocytes (and glial cells in general) in their prefrontal cortex, in the amygdale, the hippocampus (Czeh, Di Benedetto, 2013).
Taken together all the evidence suggests that astrocytes play an important role in exhibiting depression. A dysfunction in their links with neurons can cause less glutamate production, less NT release, as well as lower rates of synaptic transmission and of AHN, all of which are biological manifestations of depression. Moreover, dysfunctions in astrocytic networks also play a major role in depression: blocking of the gap junctions, thus of the communication between astrocytes can lead to depressive behaviour, while on the other hand, depression (or CUS) leads to a decreased number of astrocytes, therefore less elaborate networks, and to lower levels of connecting proteins (such as Cx43 and GFAP). Finally, many of these effects are reduced with the administration of antidepressants, which may target astrocytes indirectly.
More research is definitely necessary, but even now the link of astrocytes to depression and their overall important role in mental health is apparent.
Literature
Abbott, N., J., Hansson, E., Ronnback, L. (2006). Astrocyte- endothelial interactions at the blood- brain barrier. Nature Reviews, 7, 41-53
Aimone, J., B., Deng, W., Gage, F., H. (2010). New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nature Reviews, 11 (5), 339-350
Araque, A., Navarrete, M., Perea, G. (). Tripartite synapses: astrocytes process and control synaptic information. Trends in Neurosciences, 32 (8), 421-431
Banasr, M., Behar, K., Chowdhury, G., Duman, R., Newton, S., Sanacora, G., Terwilliger, R. (2010). Glial pathology in an animal model of depression: reversal of stress- induced cellular, metabolic and behavioral deficits by the glutamate- modulating drug riluzole. Molecular Psychiatry, 15, 501-511
Bergersen, L., H., Bezzi, P., Bhaukaurally, K., Domercq, M., Gundersen, V., Jourdain, P., Marute, C., Santello, M., Tonello, F., Volterra, A. (2007). Glutamate exocytosis from astrocytes controls synaptic strength. Nature Neuroscience, 10 (3), 331-339
Czeh, B., Di Benedetto, B. (2013). Antidepressants act directly on astrocytes: evidences and functional consequences. European Neuropsychopharmacology, 23, 171-185
Giaume, C., Holcman, D., Koulakodd, A., Rouach, N., Roux, L. (2010). Astroglial networks: a step further in neuroglial and gliovascular interactions. Nature Reviews, 11, 87-99

Mechawar, N., Nagy, C., Torres- Platas, S., Turecki, G., Wakid, M. (2016). Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides. Molecular Psychiatry, 21, 509-515

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