McLean Hospital 115 Mill Street Belmont, MA 02478
Darrick T. Balu, PhD, grew up in New York City where he earned his undergraduate and Master’s degrees. After receiving his PhD from the University of Pennsylvania, he was awarded the Division 28: Psychopharmacology and Substance Abuse Outstanding Dissertation Award from the American Psychological Association. Dr. Balu joined McLean Hospital as a post-doctoral fellow in 2008, was promoted to instructor in 2012, and to assistant professor in 2014. He is now director of his own laboratory.
Dr. Balu has been the recipient of travel awards from the American College of Neuropsychopharmacology and the Society of Biological Psychiatry (Chair’s Choice). He has also been selected to participate in several Cold Spring Harbor Laboratory courses and is a member of the Societies for Neuroscience and Biological Psychiatry.
Dr. Balu’s Translational Psychiatry Laboratory, founded in the fall of 2015, uses a wide array of cutting-edge tools (i.e., mouse genetics and viral techniques, biochemistry, molecular biology, immunohistochemistry, and behavior) to understand the neurobiological mechanisms that underlie the synaptic and behavioral abnormalities associated with psychiatric disorders, such as schizophrenia. Dr. Balu aims to use these insights into the pathophysiology of disease to test compounds for potential therapeutic effects in his models.
Schizophrenia is a chronic, severe mental disorder that affects millions of Americans. Like other psychiatric and developmental disorders, schizophrenia is a disorder of complex genetics. Multiple risk genes of modest effects interact with the environment to cause the illness. Dr. Balu is interested in better understanding a particular excitatory neurotransmitter system in the brain, and using this information to gain new insights into the underlying causes of schizophrenia.
Dr. Balu and his staff utilize mouse models carrying mutations in genes that have been associated with schizophrenia, to determine how these genetic changes lead to abnormalities in brain structure and function, and ultimately behavior. They then test the ability of novel drugs to normalize the pathologies in their models with the hope of finding better treatments for schizophrenia.
The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor that is widely distributed throughout the brain. What makes the NMDAR unique is that in addition to the binding of its agonist glutamate, NMDAR activation requires the binding of a co-agonist—either glycine or D-serine. D-serine is converted from L-serine by the enzyme serine racemase (SR). Using novel immunofluorescent techniques, the lab recently demonstrated that SR and D-serine are almost exclusively located in neurons (excitatory and inhibitory), both in mouse and humans; contrary to the previous belief that SR is predominantly astrocytic. Future studies will be aimed at determining the significance of SR and D-serine containing GABAergic neurons, and whether they can modulate excitatory input via NMDAR GMS agonist availability, which could fundamentally change our understanding of how inhibitory neurons regulate brain activity. New lines of investigation are aimed at understanding processes that regulate the expression of SR, and in turn, D-serine synthesis. For example, Pavlovian threat conditioning and extinction, both of which are dependent on NMDAR activity, up-regulate SR and D-serine. These changes occur in the brain regions important for these behaviors including the amygdala and prefrontal cortex.
There is an abundance of genetic, clinical, and pre-clinical evidence suggesting that impaired NMDAR function is a major etiological factor contributing to the development of schizophrenia. Dr. Balu and his staff have shown that mice with a genetic deletion of SR recapitulate many of the brain (i.e., reduced dendritic spines and gray matter volume in the hippocampus and cortex) and behavioral abnormalities observed in schizophrenia. In addition to SR knockout mice, Dr. Balu’s laboratory studies dysbindin knockout mice that also have impaired glutamatergic transmission to identify disturbances in common final pathways regulated by NMDAR activity that contribute to impairments in neuroplasticity, and to determine whether these deficiencies can be reversed by pharmacological intervention.
Balu DT, Li Y, Puhl MD, Benneyworth MA, Basu AC, Takagi S, Bolshakov VY, Coyle JT. (2013) Multiple risk pathways for schizophrenia converge in a mouse model of NMDA receptor hypofunction. Proceedings of the National Academy of Sciences of the United States of America 2013;110(26):E2400-9.
Balu DT, Li Y, Takagi S, Presti KT, Ramikie TS, Rook JM, Jones CK, Lindsey CW, Conn JP, Bolshakov VY, Coyle JT. An mGlu5 positive allosteric modulator rescues the neuroplasticity deficits in a genetic model of NMDA receptor hypofunction relevant to schizophrenia. Neuropsychopharmacology 2016;41(8): 2052-61.
Wolosker HW, Balu DT, Coyle JT. The rise and fall of the D-serine-mediated gliotransmission hypothesis. Trends in Neurosciences 2016;39(11):712-721.
Belmont campus - Mailman Research Center, Room 322