Assistant Professor of Psychiatry,
Harvard Medical School
Division of Behavioral Biology
Research in my laboratory focuses on understanding the mechanisms mediating dopamine-glutamate interaction and the neurobiology of addiction. Interplay between dopamine and glutamate systems underlies movement, mood, memory, and reward, and has been implicated in multiple neurological and psychiatric disorders. Dopaminergic and glutamatergic terminals converge onto the same dendritic spines of postsynaptic cortical or striatal neurons, forming "synaptic triads" among them. We are interested in understanding the molecular and synaptic mechanisms that mediate the dopamine-glutamate interaction. Using molecular, cellular, and biochemical approaches, we are identifying and characterizing the regulatory mechanisms that govern the targeting, anchoring, and function of different dopamine receptors in sites of glutamatergic transmissions. Applying whole-cell patch-clamp techniques in mouse brain slices, we are investigating the gating, enabling, or selective filtering effects of dopamine on the plasticity of excitatory and inhibitory synapses.
Another area of our research focuses on the neurobiology of reward and addiction in rhesus monkeys. Drug abuse is a major problem worldwide with grave medical and socioeconomic consequences, but the underlying molecular mechanisms remain largely unknown. A prevailing theory is that repeated drug exposure imposes persistent neurochemical and molecular changes in the reward circuitry, and that these adaptations contribute to the manifestations of addiction. using gene expression analysis tools, including microarray-based genome-profiling, and RNAi-mediated in vivo gene silencing, we are characterizing cocaine-induced gene expression alterations and the functional significance of these adaptations in various phases of addiction (initial exposure, compulsive drug seeking, and relapse) using rhesus monkey self-administration models.
Yao, W-D and Wu, C-F. The Auxiliary Hyperkinetic beta
Subunit of K+ Channels: Regulation of Firing Properties and K+ Currents in Drosophila
Neurons. Journal of Neurophysiology 1999; 81:2472-2484.
Yao, W-D, Rusch, J, Poo, M-m and Wu, C-F. Spontaneous
Acetylcholine Secretion from Developing Growth Cones of Drosophila Central Neurons in
Culture: Effects of cAMP-Pathway Mutations. Journal of Neuroscience 2000;
Torres, GE*, Yao, W-D*, Mohn, AR, Quan, H, and Caron,
MG. Functional Interaction between Monoamine Plasma Membrane Transporters and the PDZ
Domain-Containing Protein PICK1. Neuron 2001; 30:121-134. (*These authors contributed equally to this work).
Yao, W-D, Gainetdinov, RR, Arbuckle, MI, Sotnikova, TD,
Beaulieu, JM, Cyr, M, Torres, GE, Grant, SGN, Caron, MG. Identification of PSD-95 as a
Regulator of Dopamine-Mediated Synaptic and Behavioral Plasticity. Neuron 2004; 41:625-638.
Zhang J, Vinuela A, Neely MH, Hallett PJ, Grant SG, Miller GM, Isacson O, Caron MG, Yao WD. Inhibition of the Dopamine D1 Receptor Signaling by PSD-95. J Biol Chem. 2007; 282:15778-89.
Zhang JP, Xu, TX, Hallett, PJ, Watanabe, M, Grant, SGN, Isacson,O, Yao, WD. (2009) PSD-95 Uncouples Dopamine-Glutamate Interaction in the D1/PSD-95/NMDA Receptor Complex. Journal of Neuroscience, 29: 2948-2960.
Abbas AI, Yadav, PN, Yao WD, Arbuckle MI, Grant SG, Caron MG, Roth BL. (2009) PSD-95 is Essential for Hallucinogen and Atypical Antipsychotic Drug Actions at Serotonin Receptors. Journal of Neuroscience, 29: 7124-7136.
Xu TX, Sotnikova TD, Liang C, Zhang J, Jung JU, Spealman RD, Gainetdinov RR, Yao WD. (2009) Hyperdopaminergic Tone Erodes Prefrontal LTP via a D2 Receptor-operated Protein Phosphatase Gate. Journal of Neuroscience, 29:14086-14099.
Xu TX, Yao WD. (2010) D1 and D2 dopamine receptors in separate circuits cooperate to drive associative long-term potentiation in the prefrontal cortex. Proc Natl Acad Sci U S A.
107:16366-71. Epub 2010 Aug 30.