Involvement of L1 retrotransposition in midbrain dopaminergic neurons and schizophrenia.

• Applicant: Dr. Gabriela-Oana Bodea
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 265911870

Midbrain dopaminergic (MbDA) neurons are located in the ventral tegmental area (VTA) and the substantia nigra (SN) and are involved in many brain functions including motor control, reward associated behavior, cognition and modulation of emotions. MbDA neurons are implicated in various diseases such as Parkinsons disease and schizophrenia. The susceptibility of MbDA neurons to diseases is believed to be induced by environmental and genetic triggers, however the associated mechanisms are not well understood. Mobile DNA elements, such as L1 retrotransposons, which are activated by environmental and genetic risk factors, have been recently suggested to contribute to susceptibility and pathophysiology of schizophrenia and several other human diseases. L1 retrotransposons affect the genome by creating insertions, deletions and new splice sites, thereby changing gene structure and expression. Importantly, several studies suggest a link between L1 hyperactivation under stress conditions and changes in MbDA gene expression or function in schizophrenia. These changes could lead to the disease phenotype or to the exacerbation of an already incipient disease state. In this study, we propose to investigate L1 activity in MbDA neurons during development and adult life and their potential contribution to disease susceptibility. L1 expression and dynamics will be monitored in MbDA neurons at different developmental stages by using an L1-EGFP reporter mouse. We will validate these results by assessing the endogenous L1 copy number in mouse. The significance of L1 retrotransposition in human MbDA neurons will be investigated in post-mortem human adult brain sections. To examine a potential link between L1 hyperactivation in MbDA neurons and schizophrenia, we will investigate L1 activity in human post-mortem samples, from control and schizophrenic patients, and in an established mouse model for schizophrenia. Finally, we will manipulate L1 activity by using histone deacetylase or reverse transcriptase inhibitors in a mouse model for schizophrenia. We will monitor effects on the molecular and functional phenotype of MbDA neurons and on the behavior of the mice. Our study will provide important insights into L1 mobilization in MbDA neurons, and the basis for somatic retrotransposition in the mammalian brain. Moreover we expect that the results obtained will elucidate the mechanistic link between L1 retrotransposition in MbDA neurons and the etiology of schizophrenia. Increasing our understanding of the pathophysiology of schizophrenia is essential for generating more suitable treatment strategies for the disease.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Privatdozent Geoffrey J. Faulkner, Ph.D.