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Eunice Y. Yuen, Ph.D.

Research Assistant Professor

 

State University of New York at Buffalo

Department of Physiology and Biophysics (Neuroscience Program)

Buffalo, NY 14214

Tel: (716)-829-3592

Email: yeyuen@buffalo.edu

 

 

Research Interest:

 

Regulation of Glutamate Receptor Functions and Synaptic Transmission in the Central Nervous System.

 

My research focuses on the cellular mechanisms underlying glutamate receptor functions in neurons, which aims to identify useful therapeutic target for neurological disease associated with aberrant glutamate system. There are 10 billions neurons in our brain, and glutamate is the most common neurotransmitter that mediates fast, excitatory, synaptic transmission between neurons. Presynaptic terminal releases glutamate, which crosses synaptic cleft and binds to specific glutamate receptor at the postsynaptic site. Proper synaptic transmission requires precise numbers and organization of functional glutamate receptors at the synapse with an appropriate spatial and temporal manner. Interestingly, these channels are highly dynamic, which travel between intracellular compartments in response to extracellular stimulations. Alteration in the levels or localization of glutamate receptor regulates synaptic activity, thereby enhancing or suppressing synaptic strength. Many neurological disorders, such as schizophrenia, stroke, depression and anxiety, result from abnormal glutamate receptor activity in certain brain regions. However, it is still unclear about the cellular mechanisms by which glutamatergic transmission is regulated.

 

My major research goal is to elucidate the specific molecular pathways that are responsible for regulating glutamate receptor functions and synaptic transmission, which may be implicated in normal physiological or pathological processes. To pursue this, multifaceted approaches are used. First, I use electrophysiology to examine synaptic transmission in various in vitro preparations including acute brain slices, neuronal cultures and acutely dissociated single neurons. Second, I employ immunocytochemistry to visualize the changes in subcellular localization of ion channels, as well as the alterations in dendritic morphology. Third, I use cellular and molecular biology to express small interference RNA, antisense RNA, dominant negative and mutant forms of various proteins to determine the involvement of specific molecules. Forth, I perform various behavioral tests to assess whether the in vitro synaptic modulation can translate to behavior changes in vivo. Ultimately, I conduct animal surgery or genetic models to investigate whether receptor modulation is impaired in pathological conditions. Over the past five years, I have been pursuing the following research projects aim to understand cellular mechanisms that regulate glutamate receptor functions.

 

(1) Regulation by neuromodulator-mediated signaling cascades. This project aims to examine the cellular action of neuromodulators, including serotonin, dopamine and norepinephrine, in synaptic transmission. These neuromodulators are G protein-coupled receptor, which affects brain functions via distinct signaling cascades. Impairment of neuromodulator systems in certain CNS areas is found in many neurological diseases. For example, dysfunction of serotonin system involves in depression and anxiety, whereas alteration of dopamine and norepinephrine systems involves in Schizophrenia. Due to this reason, many neuropsychiatric drug targets on neuromodulators. For example, Fluoxetine is an antidepressant which is a serotonin reuptake inhibitor.  However, the cellular action and target of fluoxetine remain unclear. One of my studies was to characterize the intracellular signaling cascades that underlie the effect of neuromodulators on receptor trafficking and synaptic transmission.

 

(2) Regulation by calpain-mediated proteolysis. This project aims to understand the cellular action of calpain, a protease activated in Ca2+ dysfunction diseases, such as ischemia and Alzheimer's disease. Calpain truncates the C-terminal of glutamate receptors, yet its physiological relevance is not known. I found that calpain-cleaved glutamate receptors are internalized and degraded, which serves as a negative feedback modulation to neuronal excitability. Thus, compound that up-regulates calpain activity may potentially prevent glutamate excitotoxicity and neuronal cell death, which may serve as a useful therapeutic agent.

(3) Regulation by stress hormone. This project aims to examine the synaptic changes under acute stress condition. Neurosteroid induced by stress, such as corticosterone, induces long-term cellular changes by modulating gene transcription. Ongoing work is to examine the involved protein molecules induced by stress that is responsible for the alteration of synaptic physiology and dendritic morphology, which contribute to cognitive changes in anxiety-related disorders.

 

 

            Given the significance of synaptic modulation in normal and pathological states, results from these studies shed light on the molecular and cellular basis of glutamate synaptic plasticity, which may lead to developing novel therapeutic target for treating CNS disorders.