The MIT Project


Schizophrenia is a psychiatric disorder that affects roughly 1% of the world’s population, and for which there is no curative therapeutic.  While symptomatic schizophrenia therapeutics exist, due to a lack of understanding of how they work, these therapeutics have both debilitating side effects and lack of efficacy in a significant proportion of the patient population.  The disease is not only devastating to patients and their families, but also has a high public health burden, and therefore there is a pressing need for more effective therapeutics. 

Effective anti-psychotic drugs are thought to normalize brain cell processes that have gone awry in schizophrenia.  Given that anti-psychotic drug efficacy roughly correlates with dopamine class 2 (D2) receptor blockade, brain cell types that express these D2 dopamine receptors are a major focus for investigations that seek to understand how anti-psychotic drugs work.  A part of the brain called the striatum has the highest density of D2 receptors, and has been reported to display structural and biochemical abnormalities in schizophrenia.  An ideal pharmacological treatment would target appropriate processes in striatal cell types, and bypass other cellular processes that are associated with drug side effects.  

We hypothesize that many of the actions of antipsychotic drugs are specific to particular brain cell types.  While anti-psychotic drugs target dopamine signaling, it is likely that there exist large differences in dopamine receptor expression levels between brain cell types and similarly with the expression of the associated downstream signaling pathway components.  These expression differences will likely lead to different consequences of anti-psychotic drug treatment.  Knowledge of these differences would allow for the design of better therapeutic drugs. 

Our objective is to profile the cell type-specific actions of different classes of anti-psychotic drugs in disease-relevant cell populations.  To achieve this objective we will use the cell type-specific Translating Ribosome Affinity Purification (TRAP) methodology to reveal the translated mRNA profile – the genetic material that gets decoded and largely made into proteins -- of specific cell populations in the brain striatum upon chronic antipsychotic drug treatment.  Our studies have already revealed surprising differences in how striatal cells types respond to anti-psychotic drug treatment, and suggest that a small subset of genes are consistently targeted by all effective anti-psychotic drugs. These studies have the potential to reveal gene targets for the rational design of a new generation of therapeutics.

The Project's work is also funded in part by the JPB Foundation.



Cambridge MA


Fall 2015