The Disrupted in Schizophrenia 1 (DISC1) translocation, a mutation found across several generations of a large Scottish family, is the most promising causal genetic lesion for schizophrenia, bipolar disorder, major depression, and other psychiatric disorders. Investigating the downstream consequences of this mutation is invaluable for our understanding of the molecular basis of these major psychiatric disorders for which we currently have no diagnostic biological hallmarks. My sponsor, Dr. Xianjin Zhou, discovered that two fusion genes-DB7 and BD13, from DISC1 on chromosome 1 and Boymaw on chromosome 11-are generated by the translocation and that the fusion genes inhibit protein translation. In order to study the effects of the translocation in vivo, we have developed DISC1-Boymaw mice that express both human fusion genes. The goal of this project is to investigate the overarching hypothesis that expression of the DB7 protein causes mitochondrial dysfunction, which contributes to the phenotypes seen in the DISC1-Boymaw mice and the behavioral abnormalities associated with psychiatric disorders that have been observed human carriers of the translocation. In order to make the connection between mitochondrial dysfunction and behavior, however, we must first start with an investigation into more immediate downstream effects of mitochondrial impairment. We have proposed that the AMPK-mTOR protein translation pathway is primarily disrupted by mitochondrial impairment in the DISC1-Boymaw mice. The experiments proposed in the current application will examine two different elements in this pathway. First, I will test the hypotheses that ATP production is reduced and AMPK activation is increased in cortical parvalbumin-expressing (PV+) GABAergic interneurons of heterozygous (HET) DISC1-Boymaw mice. ATP is the energy currency of the cell and AMPK is an energy sensor that is activated due to high AMP/ATP ratio (i.e., low energy). In this project, I will focus on PV+ cortical interneurons because their high frequency firing is energetically demanding and render them particularly vulnerable to impaired ATP production. Furthermore, GABAergic interneuron impairment is consistently observed in patients with psychiatric disorders. Second, I will test the hypothesis that rDNA hypermethylation-a potential consequence of persistent mitochondrial dysfunction-contributes to the down-regulation of rRNA expression, which reduces protein translation in the DISC1-Boymaw HET mice. Specifically, I will measure rDNA methylation and general protein translation activity in PV+ cortical interneurons. Understanding the mechanisms and consequences of mitochondrial dysfunction on ATP production and protein translation in the DISC1-Boymaw mice may help elucidate the molecular pathways for the pathogenesis of schizophrenia, bipolar disorder, and major depression in the Scottish family and the general population of psychiatric patients.
Studies of the Disrupted in Schizophrenia 1 (DISC1) translocation-a genetic mutation likely responsible for schizophrenia, major depression, and other psychiatric disorders in a large Scottish family-are invaluable for molecular biologists to unravel the molecular mechanisms contributing to psychiatric disorders. The mutation causes DISC1 and its translocation partner (Boymaw) to fuse, and the expression of the DISC1-Boymaw fusion gene results in impaired function of mitochondria and inhibited protein translation in the brain. Understanding the consequences of mitochondrial dysfunction on energy production and protein translation in mice carrying the DISC1-Boymaw fusion genes will help to elucidate the molecular pathways underlying the development of psychiatric disorders in the general population.
| Higa, Kerin K; Young, Jared W; Ji, Baohu et al. (2017) Striatal dopamine D1 receptor suppression impairs reward-associative learning. Behav Brain Res 323:100-110 |
| Higa, K K; Grim, A; Kamenski, M E et al. (2017) Nicotine withdrawal-induced inattention is absent in alpha7 nAChR knockout mice. Psychopharmacology (Berl) 234:1573-1586 |
| Higa, Kerin K; Young, Jared W; Geyer, Mark A (2016) Wet or dry: translatable ""water mazes"" for mice and humans. J Clin Invest 126:477-9 |
