Molecular Basis of Bipolar Disorder

Currently, the understanding of the biochemistry of bipolar disorder is poor at best. Most recent studies are in the vein Etain et. al, 2012, in which the study revolves around elucidating abnormalities in pathways with potential links to bipolar disorder. In the case of Etain et al., the pathway in question was the melatonin biosynthesis pathway. In their study, the authors are able to show a connection between ASMT (acetylserotonin O-methyltransferase) and bipolar disorder susceptibility by screening a total of 825 bipolar patients and 892 controls in two separate studies (one set of patients and controls was from France, the other was from Germany) for a series of rare mutations in ASMT and found that certain mutations were slightly more prevalent in bipolar individuals. However, the only real outcome of the study is to make suggestions as to the significance of the ASMT in bipolar, no mechanism for its action in the disease state at a chemical level is elucidated (Etain et. al., 2012). Other studies, such as one published by Yang et al. in 2009 in Nature Molecular Psychology, looked at genes that are involved in circadian rhythm, as well as certain protein kinases that had regulatory functions in this system. Of particular interest here is the presence and significance of GSK-3, which was found in one sub-group of the experimental group to be more active due to lower levels of phosphorylation. Since GSK-3 regulates so many pathways, it could be implicated in the alterations of gene expression that the study observed (Yang et al., 2009). Unfortunately, again the best this study could do with the data they collected was to postulate that the effects on circadian rhythm were potentially involved in the disease state, but no chemical reasoning could be provided.

GSK-3 under normal conditions with magnesium ions.  generated in swiss PDB viewer.
GSK-3 under normal conditions with magnesium ions.
generated in swiss PDB viewer.

GSK-3 is also important because it is one of the most studied targets of lithium and other mood stabilizers (Klein and Melton, 1996 and Chen et al, 1999). As is mentioned in the treatment section for this disease, research into the mechanisms of Bipolar often runs backwards, from treatment to chemical understanding of the disease state. In this way, GSK-3 has been studied by probing the nature of its interaction with lithium and valproate, and subsequently the interactions of GSK-3 with other cellular proteins. A good example of this from recent literature is in Kao et al’s paper from 2013 in the Journal of Neurochemistry. In their article, the authors start by discussing the importance of fibroblast growth factor 1 (FGF1) in regulating cell proliferation, cell division, and, most importantly for this topic, neurogenesis. The authors found that treatment of the cell cultures they were using (FGF-1B and FGF1 positive and negative glioblastoma cell lines) with valproate up-regulated the expression of the FGF1 even in the FGF1 negative cells. The authors used a variety of different blotting techniques and tests to show that valproate was activating FGF-1B by inhibiting HDAC (histone deacetylase) and GSK-3 (Kao et al., 2013). In another study published in 2013, Zhang et al used a lentivirus vector expressing GSK-3beta to test the effects of over-expression of GSK-3beta in mouse brains, specifically in the hippocampal region. They found that the over-expression caused the mice to start exhibiting symptoms of depression according to the standard mouse testing procedures for models of depression (decreased sucrose preference, immobility during forced swim tests, etc) (Zhang et al., 2013)

expression of synapsin in differentiated neuron Chen et al
expression of synapsin in differentiated neuron
Chen et al 2014

Moving forward from modelling the actions of drugs in cancer cells and mice, a very recent piece of work by Chen et al published in Nature Translational Psychiatry (Chen et al., 2014) showed that a model system could be developed using induced pluripotent stem cells from bipolar patients. The authors generated dozens of cell lines which are now in cold storage for future use, and also ran tests against a control population of induced pluripotent stem cells in order to determine what the differences in transcription where between bipolar and non-bipolar cells, at each developmental step from biopsied skin cells to fully differentiated neurons. They found a huge list of proteins that were being expressed at higher or lower levels in bipolar cells, and this paper, which is discussed more in the spotlight on the main page of this website, will likely serve as the basis for several new experiments that will move our understanding of bipolar forward quite significantly.