Conte Center

Vanderbilt / NIMH Silvio O. Conte Center for Neuroscience Research

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Vanderbilt University
465 21st Avenue South
Nashville, TN 37232
For more information,
please contact Denise Malone.

2011 Pilot Grant Recipients

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Maureen Hahn, Ph.D.

Influence of Genetic Inactivation of the Norepinephrine Transporter on Serotonin Signaling
Serotonin (5-HT) and norepinephrine (NE) signaling are implicated in the processes underlying depression and anxiety and both systems are targets for the therapeutic compounds for such disorders. Evidence suggests that compounds with the ability to block both the NE and 5HT transporters (NET and SERT, respectively) may be more efficacious in treating depression than a selective serotonin reuptake inhibitor (SSRI) alone. It is not well-understood if beneficial effects of such “mixed” transporter blockers may derive from NE per se, or through influences of noradrenergic signaling on serotonergic neuronal properties. NE influences 5-HT signaling through actions at the presynaptic a2-AR heteroreceptor located on 5-HT terminals. Control of 5-HT terminal function by a2-AR heteroreceptors desensitizes in response to chronic treatment with antidepressants. This a2-AR desensitization may be a contributing factor to enhanced 5-HT tone in terminal regions following extended antidepressant treatment. These observations suggest that deficits in reuptake via NET that enhance noradrenergic signaling would generate desensitization of a2-AR heteroreceptors on 5HT terminals, thus facilitating antidepressant-like responses. Indeed, NET knockout mice demonstrate behaviors consistent with that of mice treated with antidepressants. This proposal will explore the extent to which genetically-induced NET deficiency and subsequent elevated brain NE tone alters serotonergic presynaptic properties, antidepressant response and behavior. Aim 1 will determine the effect of genetic down-regulation of NET on a2-AR heteroreceptor control of presynaptic 5-HT function. Aim 2 will determine the effects of a2-AR heteroreceptors to influence the effects of an SSRI on extracellular 5-HT levels and behavior in NET deficient mice. Overall, this work will contribute to an understanding of mechanisms underlying affective disorders and their treatment, and the contribution of individual genetic variation to these processes.

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Qi Zhang, Ph.D.

VGluT3, a Crossroad Between Glutamate and Serotonin Transmission

Three different types of vesicular glutamate transporters (VGluT1-3) have been discovered in mammalian nervous system. Among them, VGluT 1 & 2 account for the ability of most traditionally accepted excitatory neurons to release glutamate, which leaves the role of VGluT3 puzzling. Intriguingly, a series of recent findings suggested VGluT3 expression by serotonergic neurons and its association with many psychological disorders. Various hypotheses have been presented, including glutamate-serotonin co-transmission and VGluT3-facilitated serotonin release. To obtain a mechanistic understanding of VGluT3’s role in serotonergic transmission, we reason that advanced cell biology approaches such as high-resolution imaging and patch-clamp recording are required. Therefore, the aims of this pilot grant are (1) to establish a reliable culture system in which serotonergic neurons can be readily distinguished and assessed with optical imaging and electrophysiology; (2) to determine the localization of VGluT3 and VMAT in serotoninergic neurons; (3) to characterize the functional involvement of VGluT3 in serotonergic transmission. The results obtained in the proposed project will help us to set up an experimental platform on which a variety of ultra-sensitive techniques can be deployed to investigate the contribution of glutamate to serotonin transmission. Furthermore, the success of this project will open a new venue for the study of mental disorders including major depression and schizophrenia.