Astrocytic involvement in bipolar disorder

Astrocytes are crucial for the supply of glutamatergic neurons with transmitter glutamate and GABA-ergic neurons with GABA (Hertz and Zielke, 2004), and thus for glutamatergic and GABA-ergic signaling, which shows abnormalities during bipolar disorder (Cherlyn et al., 2010). Their numbers are reduced in specific cortical areas in brains from patients having suffered from bipolar disorder (Rajkowska and Miguel-Hidalgo, 2007). The three conventional antibipolar drugs, the lithium ion, carbamazepine and valproic acid have nothing in common in chemical structure and in drug action during acute treatment. However, the clinical effects of these drugs only appear after several weeks of drug administration, and studies during the last decade have demonstrated some similar brain effects during chronic treatment of rats, and these as well as additional common effects have been found in highly purified primary cultures of well differentiated mouse astrocytes. In contrast, very few common effects have been demonstrated in cultured neurons and to our knowledge none in mature neuronal cultures. Among three drugs, lithium is the only one that inhibits inositol monophosphatase, but all three drugs are found to inhibit inositol uptake in astrocytes. There are two types of inositol transporters, a high affinity Na⁺-dependent myo-inositol transporter, SMIT, and a low-affinity H⁺-dependent transporter, HMIT. At high pH value, the activity of SMIT is increased, but that of HMIT decreased. Chronic, but not acute treatment with either of the three drugs inhibits inositol uptake in astrocytes at higher concentrations of inositol, but stimulates it when the concentration of inositol is lower. As could be expected from these observations, all three drugs induce intracellular alkalization in astrocytes after chronic treatment, albeit by different mechanisms. Regulation of gene expression could also be an important adaptive response to chronic treatment with antibipolar drugs. In the brain in vivo, the majority of Ca²⁺-dependent phospholipase A₂, cPLA₂, in gray matter is located in astrocytes, and astrocytes in primary cultures express cPLA₂. All three drugs up-regulate both mRNA and protein expression of cPLA₂ after brief chronic drug treatment, but it returns to and below control levels after longer treatment. Activation of cPLA₂ by stimulation of several different neurotransmitter receptors, including 5-HT₂ receptors, and α₂-adrenergic receptors that are expressed at high levels in astrocytes, releases esterified arachidonic acid. GluK2 (GluR6) is one of the glutamate receptors that are associated with bipolar disorders. GluK2 knockout mice have mania-like behavior. This receptor is expressed at high level in astrocytes and responsible for glutamate-induced ERK phosphorylation in these cells. Chronic treatment with either one of the three drugs decreased GluK2 expression, and abolished the increase of intracellular Ca²⁺ and ERK phosphorylation by glutamate in astrocytes. Extracellular glutamate is mainly taken up by astrocytes, where it is either re-synthesized to glutamine and returned to neurons or metabolized as an energy substrate in the astrocytic TCA cycle. Lithium treatment is known to reverse an increase of extracellular glutamate in the brain of bipolar depressed patients. The lithium-induced down-regulation of astrocytic glutamate GluK2 activity may contribute to its therapeutic effect. Because of the extreme complexity of brain anatomical structure, the findings discussed above originate mainly from astrocytes in primary cultures or from experiments in vivo. The investigation of astrocytes as targets of anti-bipolar drugs will hopefully be accelerated along with the development of new techniques allowing separation of astrocytic and neuronal cell fraction from drug-treated animals and progress of research in interactions between astrocytes and neurons in the near future.