Golding Building 202
Associate Professor, Department of Molecular Pharmacology
This research program investigates the genetic basis of the regulation of synaptic transmission of the neurotransmitter serotonin. Drugs that target the serotonergic system are the most commonly prescribed therapeutic agents for the treatment of a wide spectrum of behavioral and neurological disorders, from depression to eating disorders, autism, schizophrenia and Parkinson’s disease. Using mouse and C. elegans as animal models, our laboratory is undertaking genetic dissection of the genes and biochemical pathways in serotonin signaling and characterizing therapeutics that can alter them.
One project is to identify serotonin deficient mutants in C. elegans. We have isolated a set of neuron-specific serotonin deficient (nss) mutants through unbiased genetic screens. The nss mutants offer us a unique opportunity to elucidate genetic pathways and biochemical mechanisms that regulate the development and function of specific serotonergic neurons.
A second project is to identify and characterize antidepressant-resistant genes. Using chemical mutagenesis and RNA-interference (RNAi) technology, ongoing experiments search genome-wide for mutations that confer resistance or hypersensitivity to selective serotonin reuptake inhibitors (SSRIs) in C. elegans. This screen will broadly explore SSRIs targets distinct from the known serotonin transporter and reveal downstream pathways regulated by serotonin signaling. We will translate genetic leads from C. elegans into functional analysis in mouse models.
Moussaif, M. and Sze, J. Y. (2009) Intraflagellar transport/Hedgehog-related signaling components couple sensory cilium morphology and serotonin biosynthesis in C. elegans. J. Neurosci. 29, 4065-75.
Govorunova, E.G., Moussaif, M., Kullyev, A., Nguyen, K.C., McDonald, T.V., Hall, D.H., Sze, J.Y. (2010) A homolog of FHM2 is involved in modulation of excitatory neurotransmission by serotonin in C. elegans. PLoS One. 28;5(4):e10368.
Kullyev, A., Dempsey, C.M., Miller, S., Kuan, C.J., Hapiak, V.M., Komuniecki, R.W., Griffin, C.T., and Sze, J.Y. (2010) A Genetic Survey of Fluoxetine Action on Synaptic Transmission in Caenorhabditis elegans. Genetics 186(3):929-41.
Gholamali, J., Xie, Y., Kullyev, A., Liang, B., and Sze, J.Y. (2011) Regulation of extrasynaptic 5-HT by SERT function in 5-HT-absorbing neurons underscores adaptation behavior in C. elegans. J. Neurosci. 31, 8948-57.
Chen, X.N., Margolis, K.J., Gershon, M.D., Schwartz, G.J. and Sze, J.Y. (2012) Reduced serotonin reuptake transporter (SERT) function causes insulin resistance and hepatic steatosis independent of food intake. PLoS One, 7(3):e32511.