Resting Glutamate Levels and Rapid Bursts of Glutamate Release in the Prefrontal Cortex of the Flinders Sensitive Line Rat-A Genetic Rodent Model of Depression

Overview & Synopsis

Despite the numerous drugs targeting biogenic amines for major depressive disorder (depression) the search for novel therapeutics continues due to their poor response rates (~30%) and slow onset of action (2-4 weeks). To better understand glutamate's role in depression, we utilized an enzyme-based microelectrode array (MEA) that was selective for glutamate measures with fast temporal (2 Hz) and high spatial (15 x 333 µm) resolution. These MEAs were chronically implanted into the prefrontal cortex of 3-6 month and 12-15 month Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats, a validated genetic rodent model of depression. While no changes in glutamate dynamics were observed between 3-6 month FRL and FSL rats, a significant increase in resting glutamate levels was observed in the 12-15 month FSL rats compared to the 3-6 month FSL and age-matched FRL rats on days 3-5 post-implantation. Our MEA also recorded, for the first time, a unique phenomenon in all four rat groups of fluctuations in resting glutamate that we have termed glutamate transients. While these events lasted only seconds, they did occur throughout the testing paradigm. The average concentration of these glutamate burst events was significantly increased in the 12-15 month FSL rats compared to 3-6 month FSL and age-matched FRL rats. These studies lay the foundation for future studies of both tonic and phasic glutamate signaling in rat models of depression to better understand the potential role of glutamate signaling in depression.