Targeting astrocytes in bipolar disorder

Abstract

Astrocytes are homeostatic cells of the central nervous system, which are critical for development and maintenance of synaptic transmission and hence of synaptically connected neuronal ensembles. Astrocytic densities are reduced in bipolar disorder, and therefore deficient astroglial function may contribute to overall disbalance in neurotransmission and to pathological evolution. Classical anti-bipolar drugs (lithium salts, valproic acid and carbamazepine) affect expression of astroglial genes and modify astroglial signalling and homeostatic cascades. Many effects of both antidepressant and anti-bipolar drugs are exerted through regulation of glutamate homeostasis and glutamatergic transmission, through K(+) buffering, through regulation of calcium-dependent phospholipase A2 (that controls metabolism of arachidonic acid) or through Ca(2+) homeostatic and signalling pathways. Sometimes anti-depressant and anti-bipolar drugs exert opposite effects, and some effects on gene expression in drug treated animals are opposite in neurones vs. astrocytes. Changes in the intracellular pH induced by anti-bipolar drugs affect uptake of myo-inositol and thereby signalling via inositoltrisphosphate (InsP3), this being in accord with one of the main theories of mechanism of action for these drugs.

Leaky brain in neurological and psychiatric disorders: Drivers and consequences

“…Notably, lithium and other medicines used to treat BD, such as carbamazepine and valproate, modify the expression of several astroglial genes leading to positive shift in astroglial signalling and CNS homeostasis. It is tempting to speculate that such changes could improve the structure and function of the NVU, although it must be stressed that, to date, there is no evidence to support this hypothesis (Peng et al, 2016).…”

Biphasic Regulation of Caveolin-1 Gene Expression by Fluoxetine in Astrocytes: Opposite Effects of PI3K/AKT and MAPK/ERK Signaling Pathways on c-fos

“…Astroglial contribution to major depression (similarly to other psychiatric pathologies—see Verkhratsky et al, 2014 ) does not involve astrogliosis and hypertrophy being mainly manifested by a decrease in astroglial numbers and their hypotrophy. Previously we found that fluoxetine, as well as other selective serotonin reuptake inhibitors (SSRIs) act as agonists of 5-HT 2B receptors in astrocytes (Li et al, 2008 ; Zhang et al, 2010 ; Peng et al, 2016 ). Astrocytes in cultures and in the brain in vivo express high level of 5-HT 2B receptors (Peng and Huang, 2012 ).…”

Chronic Treatment with Anti-bipolar Drugs Down-Regulates Gene Expression of TRPC1 in Neurones

“…Given CBZ, Li + , and VPA share no similarity in chemical structures, revealing downstream effects of all three drugs is important for further understanding drug targets and the pathophysiology of the disease. We have found several genes that are regulated by chronic treatment with anti-bipolar drugs in astrocytes (for review, see Peng et al, 2016). These includes down-regulation of gene expression of glutamate kainate receptor GluK2 (Li et al, 2009), the Ca 2+ -dependent phospholipase A 2 (Li et al, 2007) and transient receptor potential channel 1 (TRPC1); a cation channel, which in astroglia is activated by ER store depletion and contributes to the store-operated Ca 2+ entry, SOCE (Yan et al, 2013).…”