Takahiro Kato

By Noriaki Sagata, Yasunari Sakai and Takahiro A. Kato

Direct conversion techniques, which generate induced-neuronal (iN) cells from human fibroblasts in less than two weeks, are expected to discover unknown neuronal phenotypes of neuropsychiatric disorders. Here, we present unique gene expression and cell morphology profiles in iN cells derived from neurofibromatosis type 1 (NF1) patients. NF1 is a single-gene multifaceted disorder with relatively high co-occurrence of autism spectrum disorder (ASD). Adenylyl cyclase (AC) dysfunction is one of the candidate pathways in abnormal neuronal development in the brains of NF1 patients. In our study, microarray-based transcriptomic analysis of iN cells from healthy controls (males) and NF1 patients (males) revealed significantly different gene expression of 149 (110 were upregulated and 39 were downregulated). In iN cells derived from NF1 patients (NF1-iN cells), there was a change in the expression level of 90 genes with the addition of forskolin, an AC activator. Furthermore, treatment with forskolin dramatically changed the cell morphology, especially that of NF1-iN cells, from flat-form to spherical-form. Current pilot data indicate the potential therapeutic effect of forskolin or AC activators on neuronal growth in NF1 patients. Further translational research is needed to validate the pilot findings for future drug development of ASD.

Part of the book: Clinical and Basic Aspects of Neurofibromatosis Type 1

By Shingo Enomoto and Takahiro A. Kato

Microglia play a major role in immune response in the brain. Recent progress in studies for microglia suggests that stress causes morphological alterations in microglia and affects microglial humoral release and phagocytosis. In this review, we present a molecular mechanism by which stress impacts microglia. Then, we describe current findings for the involvement of microglia in stress-related mental disorders including posttraumatic stress disorder (PTSD), depression, and pain enhancement. We focus on preclinical and clinical studies. Preclinical PTSD studies using animal models with fear memory dysregulation show neuroinflammation by microglia and altered microglial phagocytosis, two imaging studies and a postmortem study assessing neuroinflammation in PTSD patients show contradictory results. Imaging studies suggest neuroinflammation in depressed patients, postmortem studies show no microglial inflammatory changes in non-suicidal depressed patients. Although it has been established that microglia in the spinal cord play a pivotal role in chronic neuropathic pain, several preclinical studies suggest microglia also participate in stress-induced pain. A clinical study with induced microglia-like (iMG) cells and an imaging study indicate neuroinflammation by microglia in fibromyalgia patients. We believe that progress in interactive research between humans and animals elucidates the role of microglia in the pathophysiology of stress-related mental disorders.

Part of the book: Stress-Related Disorders