The syncytiopathy hypothesis of depression: Downregulation of glial connexins may protract synaptic information processing and cause memory impairment
Introduction
The core symptoms of depression are depressed mood, diminished interest or pleasure, disturbance of circadian rhythms, psychomotor disturbances (retardation or agitation), feelings of insufficiency [1] and cognitive impairment [2]. Since most of the effective treatments of depression were discovered by empiricism, the effectiveness of somatic treatment has propelled neurotransmitter theories rather than vice versa [3]. My approach is contrary to this trend by deducing the pathophysiology of depression from an experimentally based theoretical model.
First of all, not only neuronal cells are organized into networks, but also glial cells, the second main cell type of the brain, called syncytium. I hypothesize that disorders in the glial syncytium represent a main component of the pathophysiology of depression. I speak of a syncytiopathy of depression. Although biological depression research has identified microstructural abnormalities in the white matter of the brain [4], it rarely refers to glial–neuronal units (tripartite synapses) or to the glial syncytium [5], [6], [7].
Section snippets
Hypothesis
Astrocytes interconnected via gap junctions build an astrocytic syncytium. Gap junctions are composed of connexin proteins that are activated by substances of the neuronal system. Gap junctions are regarded as the primary pathway underlying propagation of Ca2+ waves between astrocytes. In the astrocytic syncytium the expression of connexins and the expression of the various astrocytic receptor types are regulated by complex transcriptomic networks.
If the expression of connexins is
Outline of an astrocytic syncytium
Different connexins allow communication between diverse cell populations or segregation of cells into isolated compartments according to their pattern of connexin expression. Gap junctions are composed of hemichannels (connexons) that dock to each other via their extracytoplasmic extremities. Each hemichannel is an oligomer of six connexin proteins (Cx). In the central nervous system, cell-specific and developmentally regulated expression of eight connexins has been demonstrated [8].
My
Experimental evidence for downregulation of connexins and upregulation of astrocytic receptors
Connexin 43 (Cx43) is the most abundant gap junction protein in brain, where it is found primarily between astrocytes. Experimental data indicate a surprisingly high degree of impact of deletion of Cx43 on other astrocyte genes, implying that gap junction gene expression alters numerous processes in addition to intercellular communication [11]. Generally, mutations in connexin genes or altered expression of wild-type gap junction proteins may play important roles in the pathogenesis of various
Model of a tripartite synapse
According to the prevailing view, chemical synaptic transmission exclusively involves bipartite synapses consisting of presynaptic and postsynaptic components and a synaptic cleft, in which a presynaptically released neurotransmitter binds to cognate receptors in the postsynaptic cell. However, there is a new wave of information suggesting that glia, especially astrocytes, are intimately involved in the active control of neuronal activity and synaptic information transmission. Already in 1999,
Delayed synaptic information processing caused by a downregulation of astrocytic connexins may be responsible for the pathophysiology of depression
Fig. 3 shows the main effects on synaptic information transmission if the expression of connexins in the astrocytic syncytium is downregulated. (For the sake of clarity the function of the various substances like ions is omitted.) In comparison to an undisturbed tripartite synapse, depicted in Fig. 2, where the number of receptors and the amount of neurotransmitters is balanced, in the case of downregulation of the expression of astrocytic connexins, an upregulation of the expression of
Downregulation of the expression of astrocytic connexins may cause memory impairment in depression
Most patients with a major depressive episode are suffering from memory impairment [2]. Recently, significant correlations between depression severity and cognitive performance were found especially in the domains of memory [25]. Memory impairment in depression can be deduced from the model of an astrocytic syncytium as shown in Fig. 1. First of all, the communication pathways are highly dynamic [26]. If gap junctions between astrocytes are frequently coupled, dependent on their activation by
Testing the hypothesis
Recently, there has been a significant increase in studies involving astrocytic gap junctions. These have demonstrated astrocytic networks (syncytia) in the juvenile brain and a gap junction mediated astrocytic network in the mouse barrel cortex [31]. These studies are reminiscent of the study of neuronal tracts and pathways almost a century ago. Although it is presently not possible to visualize all of the plaques and constituent connexins of gap junctions in the entire brain simultaneously in
Conflict of interest statement
None declared.
Acknowledgements
I am very indebted to James Robertson for the current discussion of experimental findings in gliobiology and for the concept of syncytiopathy. I am also very grateful to Birgitta Kofler-Westergren for preparing the final version of the paper.
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