Bipolar Disorder

Abstract

This review focuses on recent advances made towards understanding the neurobiology of bipolar disorder (BD), a chronic neuropsychiatric illness characterized by altered mood and energy states. The past few years have seen the completion of the largest genetic studies by far, which have emphasized the polygenic nature of BD as well as it's connection to other psychiatric illnesses. Furthermore, the use of inducible pluripotent stem cells has rapidly expanded. These studies support previous work that implicates dysregulation of neurodevelopment, mitochondria, and calcium homeostasis, while also allowing for investigation into the underlying mechanisms of individual responsivity to lithium. Sleep and circadian rhythms have also been heavily implicated in BD, from disruptions in activity patterns to molecular abnormalities.

Figure 1.. Factors contributing to the neurobiology of BD

Recent advances in the neurobiology of BD are discussed, some of which are highlighted here. (A) Environmental risk factors implicated in the neurobiology of BD, many of which are associated with neurodevelopmental time-periods. Later environmental factors, like childhood maltreatment and sleep/activity disruptions are associated with both a higher risk of a BD diagnosis as well as increased severity of symptoms. (B) A simplified, theoretical example of BD course of illness, in which individuals experience episodes of Mania (or Hypomania) and Depression, broken up by periods of Euthymia in which few/no mood symptoms are present. Notably, symptoms and course of illness varies greatly between individuals. (C) BD is highly heritable, and recent advances in the genetics of BD support a role for dysregulation in synaptic biology, calcium signaling, and neurodevelopment. CACNA1C is a gene that has been implicated for many years in BD, while AKAP11 was identified in the most recent WES as a shared risk factor for BD and SZ. (D) Sleep and circadian rhythms are associated with both genetic and environmental risk in BD. Disrupted sleep and activity rhythms are a key diagnostic feature of the illness, and studies have now observed abnormal molecular rhythms in human postmortem brain tissue, fibroblasts, and iPSC-derived NPCs. Animal models of genetic and environmental circadian disruptions lead to behaviors associated with mood disorders. A simplified model of the core transcriptional-translational clock is presented. BMAL1 dimerizes with CLOCK (or NPAS2), facilitating its’ transcription factor activity. This leads to transcription of core clock proteins like period (PER) and cryptochrome (CRY), as well as other clock-controlled genes (CCGs). Notably, CCGs can vary greatly depending on tissue, cell-type, and species. As PER and CRY accumulate in the cytosol, they dimerize and are shuttled back into the nucleus. In the nucleus, the PER:CRY dimer inhibits BMAL1:CLOCK promoter binding, leading to inhibition of BMAL1-regulated transcription. As this transcription decreases, so does PER and CRY expression, leading then to the disinhibition of BMAL1-meidated transcription. This overall process takes 24 h, creating a 24 h negative feedback loop. (E) The mood stabilizers lithium and valproate (VPA) have been in use as treatments in BD for decades, and while they have many targets, reduction of inositol is one they share. The inositol signaling pathway interacts with G_q -mediated signaling. Specifically, in response to a ligand, the α_q subunit of a g-protein coupled receptor will bind to protein lipase C (PLC). This complex will then hydrolyse phosphatidylinositol 4,5-biposphate (PIP₂) into inositol-1,4,5 triphosphate (IP₃) and 1,2-dacylglycerol (DAG). DAG moves on to associate with Protein kinase A and stimulate a second messenger signaling cascade. IP₃ is released into the cytosol, where it can stimulate Ca²⁺ release from the ER or be broken down into inositol biphosphates (IP₂). IP₂ is then broken down into inositol monophosphoate (IP) by inositol phosphatase (IPPase), and finally into myo-inositol by inositol monophosphatase (IMPase). Lithium acts by inhibiting the enzymes IPPase and IMPase, leading to depletion of myo-inositoll, which then has major consequence on downstream GPCR, IP3/DAG signaling. (F) Mitochondria have been implicated in BD in many studies. Collectively, these point reduced mitochondria-driven ATP production and a shift towards glycolysis. Created with Biorender.