This research program investigates the genetic basis for the regulation of neural circuitry by the neurotransmitter serotonin. Dynamics of serotonin signaling underscore long-standing theories of neural circuit plasticity that leads to learning, memory and stress responses. Drugs that target the serotonergic system are the most commonly prescribed therapeutic agents for the treatments 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 a systematic dissection of the genetic pathways and synaptic properties regulated by serotonin signaling and characterizing drugs that might alter them.

One project is to delineate the role of serotonin uptake transporter SERT, the major molecular target of selective serotonin reuptake inhibitors (SSRIs), in early life programing of CNS circuits. We have identified a SERT mechanism operating specifically in the developing sensory cortices, prefrontal cortex and hippocampus during a period that lays down adult neural circuits. Specifically, SERT is transiently expressed in a unique class of neurons, termed “serotonin-absorbing neurons”, which do not synthesize serotonin but absorb it from extracellular space. We found that spatiotemporal SERT expression in the serotonin-absorbing neurons dictates the patterning of synaptic architecture. The timing and the brain regions of serotonin-absorbing neuron function coincide closely with “a key point of convergence” of coexpression network of high-confidence of autism candidate genes in human developing CNS. We hypothesize that disrupting SERT function in the serotonin-absorbing neurons by genetic variations, environmental conditions and drugs perturbs spatial and temporal levels of trophic serotonin that regulates the neural networking implicated in autism. Using our unique SERT conditional knockout mice, we are investigating how disrupting SERT expression in serotonin-absorbing neurons impacts on the expression and function of autism candidate genes, aspects of the synaptic properties in the sensory cortices, prefrontal cortex and hippocampus, and anxiety-related behavior. These studies are expected to reveal the developmental origin of SERT, thus serotonin, in the trajectory of neural circuit function, behavior, and related disorders. We will translate genetic leads from the mouse models into human studies.

A second project is to identify and characterize antidepressants-resistant genes. Using chemical mutagenesis and RNA-interference (RNAi) technology, ongoing experiments search genome-wide for mutations that confer resistance or hypersensitivity to antidepressants in C. elegans. This screen will broadly explore drug targets distinct from SERT and reveal downstream pathways regulated by serotonin signaling. We will translate genetic leads from C. elegans into functional analysis in mammalian systems.

Soiza-Reilly, M., Meye, F.J., Telley, L., Olusakin, J., Petit, E., Chen, X., Mameli, M., Jabaudon, D., Sze, J.Y., Gaspar, P. (2018) SSRIs target prefrontal-raphe circuits during development to modulate synaptic connectivity and emotion behavior. Molecular Psychiatry, In Press.

Brindley RL, Bauer MB, Walker LA, Quinlan MA, Carneiro AMD, Sze JY, Blakely RD, Currie KPM. (2018) Adrenal serotonin derives from accumulation by the antidepressant-sensitive serotonin transporter. Pharmacol Res. S1043-6618(18)30429-8.

Chen, X.N Petit, E.I., Dobrenis, K., and Sze, J.Y. (2016) Spatiotemporal SERT expression in cortical map development, Neurochemistry International, 98, 129-137.

Joo, J.H., Wang, B., Frankel, E., Ge, L., Xu, L., Iyengar, R., Li-Harms, X., Wright, C., Shaw, T.I., Lindsten., T., Green,D. R., Junmin Peng. J., Hendershot, L., Kilic, F. Sze, J.Y., Audhya, A., and Kundu, M.  (2016) Non-Canonical Role of ULK/ATG1 in ER-to-Golgi Trafficking is Essential for Cellular Homeostasi. Molecular Cell, 62, 491-506. 

Xu, L., Choi, S., Xie, Y., and Sze, J.Y. (2015) Cell-autonomous Gβ signaling defines neuron-specific steady state serotonin synthesis in Caenorhabditis elegans. PLoS Genetics 11(9):e1005540.

Chen, X.N, Ye, R., Blakely,  R.D., Gargus J.J., Dobrenis K.,  and Sze, J.Y. (2015) Disruption of transient serotonin accumulation by non-serotonin-producing neurons impairs cortical map development. Cell Reports, 10, 346-358.

Xie Y., Moussaif M., Choi, S., Xu, L. and Sze, J.Y. (2013) RFX transcription factor DAF-19 regulates 5-HT and innate immune responses to pathogenic bacteria in C. elegans.  PLoS Genetics, 9(3):e1003324.

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.

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.

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.

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.

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.