Mitochondria provide nearly all of the energy for synaptic transmission, maintenance of ionic homeostasis in synaptic terminals, development of neuronal spines, and long term potentiation which are all essential for brain function. In addition to these neuronal roles, mitochondria regulate cell survival, react to oxidative stressors, and provide ATP for most cellular functions. It is estimated that a single cortical neuron utilizes 109 molecules of ATP each second. In our initial grant, we found strong evidence of mitochondria dysfunction in schizophrenia, compared to weaker evidence for dysfunction in bipolar disorder. We conservatively estimated mitochondria DNA content heritability (h2 = 0.37), and found a highly significant decrease of mitochondria DNA in schizophrenia compared to controls and bipolar disorder. Our studies have also shown decreased gene expression and common deletion, in schizophrenia, but not in bipolar disorder, compared to controls. We have postulated a polygenic model that nuclear and mitochondrial genes interact to alter mitochondria content in periphery and in brain. This decrease in mitochondria in brain, could account for significant decreases in density of spines, especially prominent in layer III. We will further test this model, that mtDNA content is heritable, and under genetic control. We will also test association of mtDNA content with symptoms of schizophrenia. Since our initial studies have been conducted in chronic subjects with schizophrenia, we are renewing our grant to study subjects with first episode psychosis for evidence of the mitochondria dysfunction before onset of antipsychotic drug treatments. The overarching hypothesis is that the pathophysiology of SZ is associated with a reduction in mitochondrial function specifically in the localization and copy number of mitochondria in dendrite and axon locations compared to controls. The cause of the dysfunction postulated in our model is polygenic variation in both nuclear and mitochondrial genes that contribute to mitochondria copy number trait and function. We will test for association of mitochondria DNA copy number in both nuclear and mitochondrial SNPs in first episode psychosis and chronic psychosis, using blood and postmortem brain, and extend our investigations of postmortem brain to medication free individuals with schizophrenia, including bipolar disorder subjects for specificity of findings. To be confident that chronic treatment with antipsychotic drugs (APDs) does not alter mitochondria localization, we propose to study a cohort of non-human primate brains at cellular resolution, already chronically treated with APDs. Since synaptic terminal activity is dependent upon mitochondria function, we will compare the numbers of mitochondria located in postsynaptic spines in individuals with schizophrenia and controls, and APD treated rhesus monkeys compared to controls. Finally, we will assess whether APD treatment alters mitochondrial copy number, intraneuronal motility, and membrane potential in fibroblast-induced pluripotent stem cells reprogrammed into neurons from first episode psychosis subjects compared to controls. The outcomes of this study will expand our knowledge of genetic basis for mitochondria dysfunction in schizophrenia, and association of that dysfunction with psychiatric symptoms.
Mitochondria, the energy powerhouses in each brain cell, are changed in schizophrenia, and reduced in function according to multiple studies. It is unknown if the alterations are primarily caused by illness, genetics, or antipsychotic drug treatment. We propose to study mitochondria in subjects with schizophrenia, and early psychosis, to evaluate these specific causes.
|Hagenauer, Megan Hastings; Schulmann, Anton; Li, Jun Z et al. (2018) Inference of cell type content from human brain transcriptomic datasets illuminates the effects of age, manner of death, dissection, and psychiatric diagnosis. PLoS One 13:e0200003|
|Mittal, Kirti; Gonçalves, Vanessa F; Harripaul, Ricardo et al. (2017) A comprehensive analysis of mitochondrial genes variants and their association with antipsychotic-induced weight gain. Schizophr Res 187:67-73|
|Ramaker, Ryne C; Bowling, Kevin M; Lasseigne, Brittany N et al. (2017) Post-mortem molecular profiling of three psychiatric disorders. Genome Med 9:72|
|Orozco-Solis, Ricardo; Montellier, Emilie; Aguilar-Arnal, Lorena et al. (2017) A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate Cortex. Biol Psychiatry 82:351-360|
|Raben, Alex T; Marshe, Victoria S; Chintoh, Araba et al. (2017) The Complex Relationship between Antipsychotic-Induced Weight Gain and Therapeutic Benefits: A Systematic Review and Implications for Treatment. Front Neurosci 11:741|
|Limon, Agenor; Mamdani, Firoza; Hjelm, Brooke E et al. (2016) Targets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission. Neurosci Biobehav Rev 66:80-91|
|Schneider, Kevin; Valdez, Joshua; Nguyen, Janice et al. (2016) Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2). J Biol Chem 291:7754-66|
|Sellgren, C M; Kegel, M E; Bergen, S E et al. (2016) A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder. Mol Psychiatry 21:1342-50|
|Morgan, Ling Z; Rollins, Brandi; Sequeira, Adolfo et al. (2016) Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared Immune Alterations in Psychiatric Disorders. Microarrays (Basel) 5:|
|Zai, Clement C; Tiwari, Arun K; Chowdhury, Nabilah I et al. (2016) Association Study of Serotonin 3 Receptor Subunit Gene Variants in Antipsychotic-Induced Weight Gain. Neuropsychobiology 74:169-175|
Showing the most recent 10 out of 47 publications