Browsing School, Graduate by Author "Kallarackal, Angy Jose"
Serotonergic Modulation of Glutamate Transmission: Bridging Two Theories of DepressionKallarackal, Angy Jose; Thompson, Scott M., Ph.D. (2011)Major Depression is a debilitating disease affecting close to 10% of the world population. Although there are many antidepressant drugs available, 30% of patients are unresponsive and the rest must wait 3-4 weeks for therapeutic efficacy. The serendipitous discovery of these drugs in the 1950s initiated the monoamine theory of depression. This theory postulates that depression is caused by a depletion of synaptic serotonin and that effective therapies work by restoring this imbalance. However, the many gaps in this theory together with inefficient therapies have led to the search for a new explanation of the pathology of depression. Recent data has implicated a dysfunction of the glutamate system to be at fault for the symptoms of depression. Both of these theories have been developed independently, however I propose that they are not in fact distinct but may actually complement each other. Therefore I hypothesized that glutamatergic dysfunction underlies the etiology of depression, but that serotonin is capable of modulating glutamatergic transmission in a manner that rescues this defect. I investigated the effect of serotonin elevation on glutamate transmission and how this phenomenon may be altered in an animal model of depression. I found that elevation of endogenous serotonin activates 5-HT1BRs which in turn signal to phosphorylate glutamatergic AMPA receptors. This potentiation of the glutamatergic response is enhanced in animals subjected to chronic unpredictable stress and absent in na?ve animals chronically treated with antidepressants. This finding pointed to a decrease in basal glutamatergic transmission in depressed animals, which I confirmed by measuring AMPAR/NMDAR ratios. Finally, I found that activation of 5-HT1BRs and subsequent phosphorylation of the GluA1 subunit of the AMPAR is necessary for the therapeutic effects of antidepressants, and that phosphorylation of S831 is necessary for normal basal affective state in a number of behavior measures. Together my data present a novel pathway through which 5-HT1BR activation can specifically enhance AMPAR function in the hippocampus and provide a connection between two previously disparate theories of depression. These findings provide insight into the locus of dysfunction in depression and also point to new potential targets in the treatment of this disease.