An In Vitro Characterization of the Raphe Nucleus and the Effects of SSRIs on Synaptic Neurotransmission

Abstract

Antidepressants are traditionally used in the treatment of depression. While these drugs rapidly inhibit the reuptake of neurotransmitters in the synaptic terminal by blocking the serotonin and norepinephrine transporters, clinical efficacy can take several weeks. This phenomenon implies that antidepressants not only target neurotransmitter transporters, but have secondary down-stream effects that are important in the treatment of depression. Interestingly, depressed patients respond differently to similar antidepressant therapies, suggesting that although depression is due to a distrubance in the serotonergic neural system, alleviating depression involves more than enhancing synaptic sertonin concentration. Attention must be given to postsynaptic targets and how elevated serotonin modulates these pathways. Some studies have sought to investigate the mechanism of this delay in antidepressant responses,however, few have investigated the influence antidepressants have on synaptic neurotransmission. Dysfunction in synaptic neurotransmission can have profound affects on the functionality of the nervous system. The goal of this thesis is to evaluate the influence of antidepressants on synaptic neurotransmission. To study this question from a mechanistic standpoint, a primary neuronal co-culture system of serotonergic raphe and hippocampal neurons, was developed. The use of the co-culture neuronal system was devised to recapitulate the raphe/hippocampal pathway, an important serotonergic pathway implicated in the pathophysiology of depression, and provide a foundation in which to study how antidepressants alter synaptic function. The most widely prescribed antidepressants are those that target sertonergic systems, and so selective serotonin reuptake inhibitors were used, with the intention that alterations in synpatic function would elucidate the pathomechanism of depression treatment. The use of raphe and hippocampal neurons provide a unique oppurtunity to manipilate the presynaptic selective serotonin reuptake inhibitor target; the serotonin transporters, have a postysnptic receptors to activate, as well as have an endogenous supply of serotonin. Employing electrophysiological techniques, we found that selective serotonin reuptake inhibitors effect synaptic function by modulation of N-methyl-D-aspartic acid receptors through serotonin 1 A heteroreceptors. Understanding how selective serotonin reuptake inhibitors effect synaptic function will offer a more in depth knowledge base regarding the pathophysiology of the delayed onset of antidepressant action in clinical depression.