Blakely Lab

The Blakely Lab

The Blakely Lab: Graduate Students

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Daniel Bermingham - 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.

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Gwynne Davis - Neuroscience

7154 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.

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Elizabeth Ennis - Pharmacology

7148 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.

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Raajaram Gowrishankar - Neuroscience

7154 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.

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Alex Nackenoff - Pharmacology

71480 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.

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Meagan Quinlan - Pharmacology

7144 MRB III

My research explores the molecular underpinnings of serotonin transporter (SERT) regulation. More specifically, I am building on the discovery of multiple, functional SERT coding variants in subjects with autism spectrum disorder (ASD) that display altered regulation through PKG and p38 MAPK-linked pathways. The availability of a mouse model expressing the most common of these variants, SERT Ala56, provides a key opportunity to examine how disrupted SERT function and regulation leads to risk for ASD and other disorders associated with perturbed serotonin signaling.

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Cassie Retzlaff - Neuroscience

7148 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.

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Chelsea Snarrenberg - Neuroscience

7148 MRB III

Dysfunction of dopamine clearance in the synapse has been implicated in several neuropsychiatric diseases such as addiction and schizophrenia. An important regulator of dopamine signaling is the dopamine transporter (DAT), a presynaptic protein responsible for clearing dopamine after release. Using the model system C. elegans, am characterizing novel regulators of DAT using genetic and molecular techniques. A highly conserved, novel regulator of DAT, previously discovered by our lab, is known as swip-10. I seek to further characterize this regulator in C. elegans and elucidate the function of its mammalian ortholog, Mblac1. Given the conservation of dopamine signaling pathways from worm to man, we believe that an intensive study of the regulators of DAT in C. elegans will provide important insights regarding the control of DA signaling in both normal and disease states.