The goals of the experiments described in this proposal are to: 1) characterize the role that microRNA (miRNA) dysregulation plays in schizophrenia as a means to gaining insight into the biological underpinnings of the disorder;and 2) to manipulate miRNA levels at different stages of development in order to better understand the neurodevelopmental aspects of schizophrenia. Schizophrenia is a chronic psychiatric disorder that affects approximately 1% of the population worldwide and is characterized by a combination of affective and cognitive symptoms. The disorder is associated with significant disability and elevated mortality, and represents a large health care burden in the US. Although schizophrenia is among the most heritable of psychiatric disorders, the genetics and pathophysiology of the disorder are poorly understood, resulting in inadequate treatment options. Schizophrenia is believed to be caused by perturbations of gene networks involved in neurodevelopment and neuroplasticity. One mechanism by which large numbers of genes can be co-regulated is through microRNA (miRNA) regulation of coding RNA stability and translation. MiRNAs have an average of 300 evolutionarily conserved protein-coding targets each, and dysregulation of a single microRNA can have widespread effects on both gene expression and signaling pathway activity. Recently, several studies have identified dysregulation of miRNA expression in human schizophrenic brain tissue or mouse models of schizophrenia. We analyzed the expression of over 800 miRNAs in prefrontal cortical tissue from control and schizophrenic patients and identified a single miR, miR-132, that appears to be significantly downregulated in schizophrenia. We also confirmed that miR-132 expression is significantly reduced in a separate schizophrenic population, suggesting that miR-132 dysregulation may be a common phenotype of the disorder. In this research proposal, we will identify the miR-132 protein-coding targets that have direct biological relevancy to schizophrenia using a combination of bioinformatics and in vitro cell biology. We will then characterize changes in schizophrenia- like behaviors following inhibition of miR-132 function in the prefrontal cortex during the early postnatal period. Finally, we will manipulate miR-132 function at multiple developmental stages and characterize the effects on behavior, neuromorphology, and neuronal function in the adult. The results of these experiments will contribute both to our understanding of the role that miR-132 plays in regulating behavior and neuronal function, and to our understanding of the effects of disrupting a schizophrenia risk factor during different neurodevelopmental stages.
Schizophrenia is a psychiatric illness that affects approximately 2.4 million people in the US, but because the biological causes of schizophrenia are poorly understood, effective treatments are lacking. One mechanism of regulating a large number of genes at once is through a type of non-coding RNA known as microRNA (miRNA): changing the expression of a single miRNA can affect the expression of hundreds of protein-coding genes. In this grant, we will seek to understand the role that miR-132 plays in the behavioral abnormalities and neuropathology associated with schizophrenia with the goal of providing insight into the biological underpinnings of schizophrenia and identifying novel targets for future drug therapies.
|Shorter, Kimberly R; Miller, Brooke H (2015) Epigenetic mechanisms in schizophrenia. Prog Biophys Mol Biol 118:1-7|