Conte Center

Vanderbilt / NIMH Silvio O. Conte Center for Neuroscience Research

small new conte logo

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

2012 Pilot Grant Recipients
The Conte Center for Neuroscience Research is pleased to announce the recipients of the 2012 Conte Center Pilot Grants. This Pilot Grant Program is made possible by an endowment from the Vanderbilt School of Medicine and awards investigators annually with a budget of $20,000 for studies to further advance the knowledge of serotonin systems.

Stacks Image 507
Heidi Hamm, Ph.D.

5-HT Receptor Regulation of Synaptic Transmission By G Subunits
Serotonin has been shown to modulate a wide range of behavioral and physiological processes and as a result, is regulated by a series of complex mechanisms that ensure precise control of exocytotic release. Central to this process is the presynaptic inhibitory GPCR, the 5-HT1b receptor, which acts as a feedback regulator to modulate excitatory and inhibitory transmitter release from neurons via the actions of its Gβγ subunits. While Gβγ subunits are known to be essential in regulating this process, the role of specific G protein isoforms, as well as the distribution of these isoforms within the serotonergic pathway, is unknown. The aim of this proposal is to define the regional and subcellular distribution of Gβγ subunits throughout the central nervous system, and at serotonergic terminals, in an effort to examine the physiological contribution unique isoforms may play in modulating synaptic transmission. We hypothesize that Gβγ isoforms at terminals expressing 5HT-1b receptors exhibit distinct distribution patterns compared to non-serotonergic terminals, and that this enables specificity in the activation of effectors in order to modulate neurotransmitter release. To evaluate this, we propose to isolate serotonergic and non-serotonergic terminals by flow cytometry and apply a targeted proteomic strategy that will allow us to detect very small amounts of particular Gβ and Gγ subunits in complex tissue samples. Characterization of the localization patterns of G protein βγ subunits at synapses will provide new insight into the sorting of G Gβγ subunits to 5HT neuron terminals, which is currently unknown, and important progress into specificity of Gβγ signaling. Our studies will complement functional studies of the 5HT- and Gβγ -mediated inhibition of exocytotic release in the central nervous system. The technical advances yielded by this project will also enable localization of other proteins to 5HT terminals.

Stacks Image 508
Allison Limpert, Ph.D.

The Role of Phagocytosis in SSRI Mediated Neurogenesis

The selective serotonin reuptake inhibitors (SSRIs), which prevent clearance of serotonin (5HT) from the synaptic cleft, are widely used for the treatment of depression. Recent studies indicate that SSRIs do not exert their effects by simply increasing the levels of serotonin alone and link SSRIs treatment to an increase in neurogenesis. New neurons are rapidly generated in the hippocampal dentate gyrus of healthy adult animals and treatment with SSRIs increases this neurogenesis. Furthermore, preventing the production of new neurons by SSRIs attenuates their anti‚Äźdepressant effects in animal models. The mechanism by which these drugs promote neurogenesis is not known and is the objective of this study. Most newborn neurons in the adult undergo apoptosis and must be cleared to limit inflammatory responses. Microglia, the macrophages of the CNS, have been found to phagocytose apoptotic neural precursors; however, activation of these glia is accompanied by the release of inflammatory cytokines and has been found to impair neurogenesis. Recently, neural precursor cells themselves were demonstrated to phagocytose other dead precursor cells and the engulfment of dead cells by the neural precursors promoted further neurogenesis. SSRIs have been shown to suppress microglial activation and subsequent cytokine production, however their effects on phagocytosis either by microglia or by neural precursors has yet to be examined. We hypothesize that SSRIs promote neurogenesis by inhibiting microglial phagocytosis, thereby increasing the phagocytosis of apoptotic cells by neighboring neural precursors. We propose to test this by the following specific aims: (1) Determine if SSRIs inhibit microglia phagocytosis in vitro. (2) Determine if SSRIs cause more NPCs and less microglia to engulf dead cells in vivo. The results of this study will reveal mechanisms by which SSRIs regulate adult neurogenesis, thereby providing unique insights into the function of serotonin in the brain.

Stacks Image 509
Ran Ye, Ph.D.

Generation of a Conditional Mouse Model for Neuroligin 2 Gene Disruption

Serotonin (5-hydroxytryptamine, 5-HT) plays multiple physiological roles in the brain and periphery and is well recognized for its association with neuropsychiatric disorders including anxiety, mood disorder, Obsessive-Compulsive Disorder (OCD) and Autistic Spectrum Disorders (ASD). From proteomic screening of serotonin transporter (SERT, SLC6A4) co- immunoprecipitation (Co-IP) I identified the postsynaptic cell adhesion protein neuroligin 2 (NLGN2) as a SERT interacting protein, validated by Western blotting and immunohistochemical staining. In an effort to investigate further the functional and behavioral impact of this interaction, I propose to develop NLGN2 floxed mice that can be used to generate constitutive and inducible NLGN2 knockouts in 5-HT neurons. The proposed animal models will also be useful in generating constitutive and conditional elimination of NLGN2 in other brain regions and cell types. My hypothesis is that deletion of NLGN2 in the raphe will disrupt the negative feedback signaling of 5-HT1A receptors on 5-HT neurons due to disrupting alignment and organization of pre- and post- synaptic membrane near 5-HT synapses. The validation of this hypothesis will provide direct evidence of the involvement of a NLGN2-NRXN trans-synaptic cell adhesion protein complex in regulating 5-HT signaling and help to advance our understanding towards the contribution of cell adhesion proteins to neuropsychiatric diseases.