Evidence for alterations of the glial syncytial function in major depressive disorder

Abstract

Background Glial cells are essential in maintaining synaptic function. In glutamatergic synapses astrocytes remove the products of neural activity (i.e. potassium, glutamate and excess water) from the synaptic cleft and redistribute them across the glial network; these products of neural activity can then be recycled for neuronal use or released into the vascular compartment. This type of highly coupled cell network -or syncytium- maintains the balance of synaptic activity by restoring the basal levels of such molecules in the synaptic cleft. Previous studies have reported alterations of glia related genes in Major Depressive Disorder, including some genes related to syncytial function. Methods We used RNA isolated from hippocampal tissues of 13 MDD subjects and 10 healthy controls to broadly examine gene expression using microarrays. Hippocampal RNA samples were isolated by laser capture microdissection from human tissue sections carefully avoiding contamination from neighboring structures. Once RNA quality was validated RNA was labeled and hybridized to microarrays. Results Analysis of microarray data identified mRNA transcripts involved in glial syncytial function that were downregulated in MDD subjects compared to controls, including potassium and water channels (KCNJ10, AQP4), gap junction proteins (GJA1) and glutamate transporters (SLC1A2, SLC1A3). These gene expression differences were confirmed by qPCR. Conclusions The downregulation of these genes related to the syncytial network activity of glial cells is consistent with the hypothesis that synaptic homeostasis is disrupted thereby disrupting hippocampal synaptic function in MDD patients. Such glial gene expression changes could contribute either to the onset or perpetuation of depressive symptoms and hence, represent targets for novel therapeutics.

Vascular depression consensus report – a critical update

“…Recent studies have focused on the role of glia in LLD [162, 168], although the mechanisms by which glia are associated with the symptoms of MDD remain unclear. Inflammatory mechanisms and the role of cytokines and other pro-inflammatory markers have been suggested [169] (for a review, see [170]).…”

Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress

“…These data show that deficiency in GJA1 or GJB3 genes, which code for Cx30 and 43 respectively, does not underpin the major depression phenotype, but rather that the expression of these genes is reduced as a result of the disease. Evidence suggestive of reduced gap junction expression in astrocytes was also observed in hippocampal tissue from depressed patients (Medina et al, 2016), suggesting that the down regulation of Cx30 and Cx43 could be a brain-wide phenomenon and a general maladaptation of this disease.…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Evidence of astroglial dysfunction and immune activation in postmortem brain samples from depressed suicide victims (Nagy et al, 2015;Torres-Platas et al, 2014a;TorresPlatas et al, 2011). Hippocampal mRNA transcripts involved in glial syncytial function, including potassium and water channels (KCNJ10 and AQP4), gap junction proteins (GJA1), and glutamate transporters (SLC1A2 and SLC1A3), are downregulated in MDD subjects compared with controls (Medina et al, 2016). Association between inflammatory markers (in the plasma and CSF) and MRS-based evidence of astroglial activation-increased glutamate and myo-inositol in depressed patients .…”