Schizophrenia (SZ) is a common, chronic group of psychotic brain disorders, affecting 1% of the US population, creating a significant public health problem because of the associated disability, morbidity and mortality. The pathogenesis of SZ is poorly understood, but it is thought to be a neurodevelopmental disorder. Neuroimaging evidence has accumulated to indicate that the dorsolateral prefrontal cortex functions abnormally in SZ, both when activated and at rest. Further, EEG evidence has identified abnormalities of ? oscillations in SZ, suggesting that parvalbumin positive GABAergic interneuron regulation of cortical pyramidal neurons is dysfunctional. In the past 5 years, data have accumulated to prove that neuronal embryogenesis is accompanied by activation of LINE1 (L1) retrotransposons (RTPs) to an unexpected degree, such that each developing neuron may accumulate multiple de novo L1 RTP genomic insertions, perhaps as many as ~80. This results in a substantial mosaicism within populations of CNS neurons. While most of these somatic de novo L1 RTP insertions will have little effect on neuronal function (perhaps because they occur in gene deserts or in large introns or in genes not required for that cell's function), some may interfere with normal neuronal activity because they have inserted into a gene needed by that particular neuron for normal function. If one or more functional L1 RTP insertion events occur early in CNS development, all the daughter neurons that derive from that neuronal precursor will also carry the L1 insertion, perhaps leading to a dysfunctional population of neurons destined to increase risk for SZ. This proposal will employ CNS tissue (obtained at autopsy) from SZ patients and matched controls. Using laser capture microdissection of parvalbumin positive interneurons and their target pyramidal cells of dorsolateral prefrontal cortex, followed by high-throughput sequencing, detection of novel L1 RTP insertions will be accomplished. In this manner, it is expected that novel somatic L1 RTP insertions, which increase risk for SZ, will be discovered.

Public Health Relevance

Schizophrenia is a chronic psychotic illness and a serious public health problem, creating substantial morbidity and mortality. The goal of this project is to examine the genomes of nerve cells in brains of deceased persons with schizophrenia, to determine whether there are mutations in genes of nerve cells which might make them function improperly, giving rise to risk for schizophrenia. Identification of such mutations would create new targets for medication development and would improve our understanding of the origins of schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Molecular Neurogenetics Study Section (MNG)
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Meinecke, Douglas L
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University of Pennsylvania
Schools of Medicine
United States
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