Sivan Subburaju, PhD
Director, Laboratory for Neuromedicine Research and Discovery
- Assistant Professor of Psychiatry
Biography
Dr. Sivan Subburaju obtained his PhDs in neurobiology and neuroendocrinology, respectively, from the University of Madras and the National University of Singapore. He completed his visiting research fellow training at the National Institute of Child Health and Development, Bethesda in 2007 and joined McLean Hospital. He received the NARSAD Young Investigators Award in 2012 from the Brain & Behavior Research Foundation.
Dr. Subburaju is the director of the Laboratory for Neuromedicine Research and Discovery (LNRD) at McLean Hospital and an assistant professor of psychiatry at Harvard Medical School. He studies pathophysiological mechanisms underlying GABA and dopamine neuron dysfunction in schizophrenia, bipolar disorder, addiction, and Parkinson’s disease (PD), using a combination of biochemical, genetic, molecular, and translational in vitro and in vivo techniques.
The focus of Dr. Subburaju’s research is to understand the molecular and pathophysiological basis of brain diseases, with the ultimate goal of providing tools for earlier diagnosis and better management of disease, as well as novel therapies.
His primary goal has been to advance the understanding of neuropsychiatric and neurological disorders with a focus on the pathophysiological processes underlying GABA cell dysfunction and related cognitive impairments in schizophrenia and bipolar disorder. A related secondary focus is on disturbances of the dopamine system in the brain, especially dopamine supersensitivity and dopamine D2 receptor function, which have been implicated in neurological disorders, including schizophrenia and Parkinson’s disease.
Toward this end, Dr. Subburaju’s laboratory uses a model of early Parkinson’s disease to characterize a novel dopamine D2 receptor agonist that was developed by Dr. John L. Neumeyer. In the early stage of Parkinson’s disease, dopaminergic neurons are dying, but symptoms that would allow diagnosis are not yet visible. The death of the dopaminergic neurons, however, results in a compensatory up-regulation of dopamine D2 receptors. This effect could potentially be useful as an early biomarker, and Dr. Subburaju’s group is working to develop a highly specific and sensitive novel positron emission tomography (PET) ligand for its detection.
A second disease involving pathophysiological changes of the dopamine system is schizophrenia. Medications used to treat schizophrenia can, in some patients, lead to a supersensitivity of the dopaminergic system, including the D2 receptor, resulting in treatment resistance. A highly specific D2 receptor agonist can be utilized to detect changes in D2 receptor density and activity in schizophrenia patients using PET imaging. This would facilitate early diagnosis of drug-induced supersensitivity and also the adjustment of antipsychotic dosage to manage disease symptoms. Dr. Subburaju’s group is working on rigorously validating the ligand in vitro and in vivo to translate it into human studies.
Bipolar disorder and schizophrenia are both multifactorial mental diseases characterized by GABA neuron dysfunction in the hippocampus, specifically decreased expression of the GABA synthesizing enzyme GAD. This inhibition is accompanied by changes in other factors that are specific to each of the two disorders. Dr. Subburaju’s group has shown that targeted manipulations of these regulating transcription factors resulted in changes in GAD expression in vitro and in vivo, thus establishing a pathophysiological basis for disease associated with neuronal dysfunction.
By using a multi-level and comprehensive approach spanning from the molecular level via physiological alterations to behavioral changes, the lab is working on the chain of events linking the disturbance of GABAergic neurons to cognitive impairments, which are central to both disorders. Overall, Dr. Subburaju’s aim is to develop new RNA-based therapeutic targets via a deeper understanding of the molecular pathophysiology of these diseases.
- Abinaya Shanmugavadivu, PhD, Research Fellow
- Vadim Bolshakov, PhD, McLean Hospital
- Edward G. Meloni, PhD, McLean Hospital
- Penny Hallett, PhD, McLean Hospital
- Marc J. Kaufman, PhD, McLean Hospital
- W. Brad Ruzicka, MD, PhD, McLean Hospital
- Anna W. Sromek, PhD, Northeastern University
- Changning Wang, PhD, Massachusetts General Hospital
- Hsiao-Ying (Monica) Wey, PhD, Massachusetts General Hospital
Subburaju S, Coleman AJ, Ruzicka WB, Benes FM. Toward dissecting the etiology of schizophrenia: HDAC1 and DAXX regulate GAD67 expression in an in vitro hippocampal GABA neuron model. Translational Psychiatry. 2016;6(1):e723.
Subburaju S, Sromek AW, Seeman P, Neumeyer JL. The high affinity dopamine D2 receptor agonist MCL-536: a new tool for studying dopaminergic contribution to neurological disorders. ACS Chemical Neuroscience. 2021;12(8):1428-1437.
Ruzicka WB, Mohammadi S, Fullard JF, Davila-Velderrain J, Subburaju S, Tso DR, Hourihan M, Jiang S, Lee HC, Bendl J, Voloudakis G, Haroutunian V, Hoffman GE, Roussos P, Kellis M. Single-cell multi-cohort dissection of the schizophrenia transcriptome. Science. 2024;384(6698):eadg5136.
Education & Training
- 1981 BSc, University of Madras, India
- 1984 MSc, University of Madras, India
- 1986 MPhil, University of Madras, India
- 1995 PhD, University of Madras, India
- 1999 PhD, The National University, Singapore
- 1987-1989 Research Fellow, University of Madras, India
- 1989-1990 Senior Research Fellow, CSIR, Government of India
- 1990-1994 Research Scholarship, The National University, Singapore
- 2004-2007 Visiting Research Fellow, NICHD, National Institutes of Health
