Abstract
Bipolar disorder (BD) and schizophrenia are psychiatric disorders that manifest unusual mental, behavioral, and emotional patterns leading to suffering and disability. These disorders span heterogeneous conditions with variable heredity and elusive pathophysiology. Mood stabilizers such as lithium and valproic acid (VPA) have been shown to be effective in BD and, to some extent in schizophrenia. This review highlights the efficacy of lithium and VPA treatment in several randomized, controlled human trials conducted in patients suffering from BD and schizophrenia. Furthermore, we also address the importance of using induced pluripotent stem cells (iPSCs) as a disease model for mirroring the disease’s phenotypes. In BD, iPSC-derived neurons enabled finding an endophenotype of hyperexcitability with increased hyperpolarizations. Some of the disease phenotypes were significantly alleviated by lithium treatment. VPA studies have also reported rescuing the Wnt/β-catenin pathway and reducing activity. Another significant contribution of iPSC models can be attributed to studying the molecular etiologies of schizophrenia such as abnormal differentiation of patient-derived neural stem cells, decreased neuronal connectivity and neurite number, impaired synaptic function, and altered gene expression patterns. Overall, despite significant advances using these novel models, much more work remains to fully understand the mechanisms by which these disorders affect the patients’ brains.
Highlights
The global incidence of psychiatric disorders has increased over the past decades, placing a high socio-economic burden
They measured the intracellular Ca2+ concentration using a ratiometric fluorescence assay. Their results showed an increase in the basal Ca2+ concentration in the B lymphoblasts of Bipolar disorder (BD) type I patients compared to healthy controls, suggesting the existence of irregular calcium homeostasis in the BD patients’ lymphoblasts, especially in BD type I patients [56]. Another BD and schizophrenia model using human olfactory neuroepithelial cells obtained from four patients with schizophrenia, four patients with BD, and four control patients was developed in 2013 by Chagoyan et al They analyzed microtubule organization using neuronal progenitors by immunofluorescence method, quantified the olfactory marker protein (OMP) using western blot, and performed whole-cell recordings of voltageactivated Ca2+ currents by patch-clamp techniques on olfactory sensory neurons obtained from the olfactory neuroepithelium
Schizophrenia is a lifelong mental disorder characterized by varied symptoms that primarily involve a range of cognitive behavior and emotional dysfunctions that can manifest in the form of delusions, hallucinations, disorganized speech, excessive disorganization, catatonic behavior, and negative symptoms including poor community and social functioning [60]
Summary
The global incidence of psychiatric disorders has increased over the past decades, placing a high socio-economic burden. Human neurons derived from induced pluripotent stem cells (iPSCs) are great candidates for modeling these disorders. Investigators have been able to use many different human-derived cell culture brain models such as neurospheres [19], neurons [20], astrocytes [21], microglia [22], oligodendrocytes [23], and the recent progress in developing 3D brain organoids and specific brain organoids such as cortical [24], midbrain [25], striatal [26], and hippocampal [27]. We will focus on two psychiatric disorders, BD and schizophrenia, and on two mood stabilizers, lithium and VPA, highlighting their reported mechanism of action on various models of psychiatric disorders
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