McLean Hospital Title:
- Director, Translational Psychiatry Laboratory
Harvard Medical School Title:
- Assistant Professor of Psychiatry
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 (schizophrenia, post-traumatic stress disorder) and neurologic (Alzheimer’s disease, traumatic brain injury) disorders. 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 effect 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 various brain disorders.
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.
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. 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.
New lines of investigation are aimed at understanding how D-serine synthesized and released from reactive glia contribute to the impairments in synaptic plasticity and neurodegeneration associated with traumatic brain injury and Alzheimer’s disease, respectively. Furthermore, his lab is studying how neural activity regulates the expression of SR, and in turn, D-serine synthesis. For example, Pavlovian fear conditioning and extinction, both of which are dependent on NMDAR activity, up-regulate SR and D-serine. These changes occur in the brain regions associated with these behaviors, including the amygdala and medial prefrontal cortex. This connection between D-serine and fear extinction could have important implications for the neurobiology and treatment of post-traumatic stress disorder (PTSD).
- Sabina Berretta, MD, McLean Hospital
- Vadim Bolshakov, PhD, McLean Hospital
- P. Jeffrey Conn, PhD, Vanderbilt Center for Neuroscience Drug Discovery
- Daniel J. Liebl, University of Miami Miller School of Medicine
- Kerry J. Ressler, MD, PhD, McLean Hospital
- Herman Wolosker, MD, PhD, Technion-Israel Institute of Technology
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.
Balu DT, Pantazopoulos H, Huang CCY, Muszynski K, Harvey TL, Uno Y, Rorabaugh JM, Galloway CR, Botz-Zapp C, Berretta S, Weinshenker D, Coyle JT. Neurotoxic astrocytes express the d-serine synthesizing enzyme, serine racemase, in Alzheimer’s disease. Neurobiology of Disease. 2019;130:104511.
Wolosker H, Balu DT. D-serine as the gatekeeper of NMDA receptor activity: implications for the pharmacologic management of anxiety disorders. Translational Psychiatry. 2020;10(1) 184.
Education & Training:
- 2002 BS in Biology and Chemistry, Hofstra University
- 2004 MS in Pharmacology, Saint John’s University
- 2008 PhD in Pharmacology, University of Pennsylvania
- 2008-2012 Post-Doctoral Fellowship, Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital
Belmont campus - Mailman Research Center, Room 118