Scrutinizing an epigenetic driven dysregulation of prefrontal mGluR2 function in alcohol dependence

• Applicant: Dr. Marcus Meinhardt
• Subject Area: Biological Psychiatry
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 447264064

A key deficit in alcohol dependence is disrupted prefrontal cortex function leading to persistent drug relapse. However, the molecular events underlying the emergence of addictive responses are poorly understood. Here, we propose a critical role for the metabotropic glutamate receptor 2 (mGluR2) within the prefrontal cortex that shapes the progression into alcohol dependence as recent research demonstrates the receptor downregulation as pivotal element in the disease. Investigating the underlying mechanism of downregulation might lead to novel treatment strategies for alcohol dependence. We hypothesize an epigenetic driven disruption of mGluR2 function which ultimately causes a deterioration of prefrontal function and relapse to alcohol. We will use an integrative molecular and behavioral approach for studying the emergence of cognitive deficits and relapse in alcohol dependence, including innovative transgenic techniques in rats combined with viral vector gene transfer as well as state-of-the-art cell-type specific epigenetic investigations. Our experiments are aimed to i) manifest the role of prefrontal mGluR2 in alcohol dependence ii) investigate the mechanisms of downregulated receptor function and iii) develop treatment opportunities that restore mGluR2 function and have a high translational value.Altogether, the proposed project pursues to notably enrich our knowledge of prefrontocortical mGluR2 function in alcohol dependence and to determine and resolve region-specific mechanistic dysregulations. In a broader perspective, the proposed project will contribute to a better understanding of prefrontal function in maladaptive behaviors of neuropsychiatric diseases in general, which may finally lead to novel therapeutic approaches.

• DFG Programme: Research Grants