Daniel Bermingham - Graduate Neuroscience
7150 MRB III
The neurotransmitter dopamine (DA) is critical for numerous processes in the mammalian CNS, such as motivation, motor behaviors, and reward. Dysfunction it its signaling has been implicated in a wide variety of brain disorders such as ADHD, addiction and schizophrenia. In order to understand how dopamine signaling functions at the level of the synapse, I utilize the powerful model system Caenorhabditis elegans. The power of this system lies in the ease with which genetic manipulations can be performed both quickly and cheaply, allowing for rapid analysis of contributions of genes to various processes and behaviors. I am specifically interested in presynaptic regulation of dopamine signaling, looking primarily art the regulation and function of the C. elegans dopamine transporter Dat-1, which, like in higher organisms, acts to stop dopamine signaling through reuptake into the presynaptic terminal. I am also investigating the function of the presynaptic D2-like dopamine receptor Dop-2, and its potential interactions with Dat-1.
Gwynne Davis - Graduate Neuroscience
7150 MRB III
Dopamine (DA) signaling has been shown to be critical for a variety of critical processes, from the ability to execute movement, to reward and motivation When DA signaling is disrupted, a variety of negative consequences can occur. I am interested in the molecular and cellular changes that arise when DA signaling is genetically altered, and how such change affect behavioral output. Specifically, I am examining DA signaling in relation to ADHD, using transgenic mouse models that contain rare knock-in coding variants of the DA transporter (DAT), identified in subjects with ADHD, using behavioral, pharmacological and molecular approaches. Additionally, I am exploring how serotonin signaling responds to alterations in DA signaling and whether alterations could help explain aspects of ADHD linked to impulsivity and motivation.
Elizabeth Ennis - Graduate Pharmacology
7150 MRB III
I am investigating the molecular basis of small molecule interactions with the presynaptic, high-affinity choline transporter (CHT). The accumulation of choline by CHT at cholinergic synapses is the rate limiting step in the production of the neurotransmitter acetylcholine. Currently, there is only one small molecule known to target CHT with high-affinity and it is unsuitable as a probe for CHT in vivo. Small molecule enhancers of CHT that could boost acetylcholine production in disorders like Alzheimer's disease and reduce cognitive deficits do not exist. My project centers, therefore, on identifying such molecules using high-throughput screening techniques. I am also investigating the differential requirements for choline and Na+ flux and how CHT structure may be altered by drugs or disease-associated mutations.
Raajaram Gowrishankar - Graduate Neuroscience
7150 MRB III
The dopamine (DA) transporter (DAT) plays an important role in terminating DA signaling via reuptake of DA into the presynaptic terminal. DAT has been implicated in neuropsychiatric and neurodevelopmental disorders like ADHD and is the target of action for psychostimulants like cocaine and amphetamine. Previous work in the lab has involved the discovery and characterization ofnovel ADHD DAT coding variants. My project in the lab is to elucidate the disruptions in regulation of these novel DAT variants using a heterologous cell expression system assaying for changes in protein-protein interactions and transporter function. Additionally, I am also involved in a biochemical and physiological characterization of a knock-in mouse model expressing one of these ADHD DAT variants, A559V.
Andrew Hardaway - Graduate Neuroscience
7150 MRB III
The dopamine transporter (DAT) serves as a critical modulator of dopamine signaling, clearing dopamine (DA) from the synapses through uptake into the presynaptic terminal. Given this important role, DATs have been implicated in neuropsychiatric diseases and shown to be targeted by psychostimulants such as cocaine and amphetamines. Using forward genetics in the model system C. elegans, I hope to identify novel presynaptic regulators of DAT function that may influence its biosynthesis, trafficking to the plasma membrane, or activity at synaptic sites. Using genetic approaches combined with confocal microscopy, I am examining the importance of the DAT C-terminus in mediating synaptic localization of transporters in vivo. Multiple protein-protein interactions have been demonstrated for the DAT C-terminus in cell culture studies, but functional correlates of these interactions have not been shown in vivo. Exploration of functional interactions of DAT with these interactors in a simpler model system may provide clues to the mechanisms by which DA clearance is controlled in higher organisms.
Marc Mergy - Graduate Neuroscience
7148 MRB III
Dopamine (DA) plays a key role in regulating reward and pleasure, motor function, mood and cognition. Several neuropsychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, drug and alcohol abuse and attention deficit hyperactivity disorder (ADHD) involve an imbalance in dopaminergic tone. The dopamine transporter (DAT) acts to terminate DA signaling by removing extracellular DA from the synapse, thus maintaining the proper balance of DA neurotransmission. Previous work in the lab has identified single nucleotide polymorphisms (SNPs) in the DAT gene that result in amino acid substitutions and altered transporter function. My research continues the search for novel SNPs in the DAT gene in ADHD and bipolar disorder using a temperature gradient capillary electrophoresis method. Additionally, I am working in a heterologous cell system to characterize the functional impact of a novel DAT coding variant that I recently discovered.
Alex Nackenoff - Graduate Pharmacology
7150 MRB III
The serotonin transporter (SERT) controls synaptic levels of serotonin (5-HT) via reuptake. Selective serotonin reuptake inhibitors (SSRIs), the most well known class of antidepressants, antagonize SERT in order to increase serotonergic signaling and by doing so, lead to the alleviation of the symptoms of depression. Antidepressant efficacy, while thought to be driven by serotonergic signaling, is likely to be dependent upon many other factors. My primary research goal is to elucidate the contribution of serotonergic and non-serotonergic signaling upon SSRI efficacy. To accomplish this, I am working with transgenic mice bearing a point mutation (I172M) that confers insensitivity to many antidepressants and cocaine. This model allows me to remove the 5-HT component of SSRIs and less selective antidepressants (and cocaine) and thereby 1) clarify serotonin-specific effects and 2) identify other molecular pathways that could present novel medication targets as well as risk factors in depression. Using a different transgenic mouse model, I am also investigating the physiological and behavioral impact of adenosine receptor mediated SERT regulation.
Cassie Retzlaff - Graduate Neuroscience
7150 MRB III
Acetylcholine was the first neurotransmitter to be discovered, and the rate-limiting step in its synthesis is the presynaptic uptake of choline. The high-affinity choline transporter (CHT) is responsible for this uptake. I aim to characterize the regulation of CHT by examining transporter mutants, both natural and engineered, as well as the molecular consequences of CHT dysfunction in vitro and in vivo to gain a more complete picture of how nerve terminals regulate CHT. I hope my work can allow for a greater understanding of diseases that arise from cholinergic dysfunction.