Wei-Dong Yao, PhD
Assistant ProfessorThe New England Primate Research Center
Dopamine signaling; synaptic plasticity; neurobiology of neuropsychiatric and neurodegenerative disorders
Novel molecular targets for therapeutic modulation of addiction and neurodegenerative diseases such as Huntington’s and Parkinson’s
Although DA-based therapies are effective in alleviating some of the core symptoms of these diseases, cognitive and motivational deficits are often not fully restored. In addition, DA-based pharmacological interventions often have severe unwanted effects, such as psychosis and dyskinesias for Parkinson’s disease and extrapyramidal side effects for schizophrenia. Alterations of phasic dopaminergic transmission mediated exclusively at dendritic spines of the triads hold a key, because while exogenous DA or DA-based pharmacotherapies can in theory restore dopaminergic signaling at extraspinous loci, they can not in any simple manner restore phasic information transmitted by neuronal impulses at the synaptic triads. Thus, Dr. Yao’s findings relating to the regulatory mechanisms controlling dopamine receptor signaling in dendritic spines have far-reaching therapeutic ramifications for a variety of neuropsychiatric and neurological disorders that constitute significant unmet medical needs. Moreover, the use of non-human primate models strengthens the relevance of the data to humans. Dr. Yao is at the forefront of molecular investigations into dopamine receptor signaling, and partnering with his lab represents a unique opportunity to gain access to important advances in this clinically relevant area, with the aim of pursuing commercial development of these results.
Current Research Interests
Dr. Yao is researching several aspects of neurobiology, including addiction to psychostimulants and movement disorders such as Parkinson’s disease, at the cellular and molecular levels. His studies encompass non-human primates as well as mouse models, allowing genetic studies to be performed. Dr. Yao’s research is unveiling key regulatory aspects of dopamine signaling that affect dopamine receptor activity and the interaction between dopamine receptors and the NMDA receptor in dendritic spines, as well as novel mechanisms regulating synaptic plasticity. The ongoing projects in Dr. Yao’s lab include:
- Molecular mechanisms regulating dopamine signaling in dendritic spines, with a focus on roles of spine glutamate receptor/scaffold system
- Dopaminergic control of cortical synaptic plasticity, with a particular emphasis on the dopamine D2 receptor-mediated intracellular signaling in the prefrontal cortex
- Molecular mechanisms underlying synaptic transmission and plasticity, with a focus on novel postsynaptic density proteins
- The neurobiology of addiction in non-human primates, using gene expression profiling and viral mediated gene silencing technologies
Dr. Yao has been studying molecular and cellular facets of dopamine signaling, dopamine-glutamate interaction, and synaptic plasticity in (glutamatergic) dendritic spines. 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. The Yao lab recently reported novel roles of PSD-95, a prototypic postsynaptic scaffolding protein in spines, in regulating dopamine D1 receptor activity and in balancing a delicate interplay between the dopamine and glutamate systems in spines and synapses. Extending earlier studies that implicated PSD-95 in the behavioral response to pyschostimulants such as cocaine, the Yao lab further showed that PSD-95 directly associates with the D1 receptor, producing a suppression of receptor signaling. In addition, PSD-95, D1, and NMDA glutamate receptors are components of a multiprotein complex. Within the complex, PSD-95 inhibits the physical association between D1 and NMDA receptors and functionally uncouples D1 receptor trafficking and signaling from modulation by NMDA receptors. Thus, Dr.Yao’s studies reveal a new molecular paradigm for neuroprotection: PSD-95 acts as a check on overabundant signaling mediated by D1-NMDA receptor complexes, by interfering with D1-NMDA complexes as well as stalling the trafficking of D1 molecules to the cell surface.