Efforts to develop more effective drugs for treating schizophrenia have received a significant boost with a groundbreaking study from the laboratory of Jones Parker at Northwestern University, published recently in Nature Neuroscience. Antipsychotic drugs, commonly prescribed for millions of people suffering from schizophrenia, often come with side effects and limited efficacy. However, this study offers hope for improved treatments.
Image: Data courtesy of Jones Parker lab – Northwestern University.
Traditionally, researchers have evaluated antipsychotic drug candidates based on their impact on mouse behavior, with locomotor activity being the most commonly used predictor of clinical efficacy. The approach advanced by the Parker lab surpassed these conventional methods using the Inscopix nVista miniscope for in vivo single cell Ca2+ imaging to retrospectively predict the effectiveness of approved and failed antipsychotic drugs.
Their study unveiled a surprising revelation that challenges the long-held belief about the interaction of antipsychotic drugs and dopamine. Patients suffering from schizophrenia exhibit elevated striatal dopamine levels which are thought to disrupt the balanced activity levels of the striatum’s principal output neurons: D1 receptor and D2 receptor-expressing spiny-projection neurons (D1- and D2-SPNs).
Historically, it was thought that the therapeutic mechanism of action of antipsychotic drugs depended critically on D2 receptor antagonism on D2-SPNs. Contrary to previous assumptions, the Parker lab’s research has brought to light that a drug’s impact on D2-SPN activity may have limited relevance to its antipsychotic efficacy in humans. Instead, whether a drug modulates D1-SPN activity has a higher predictive value of its clinical effectiveness.
While the set of approved and failed drugs all looked similar according to a standard locomotor assay, each drug had different profiles based on their modulation of D1/D2-SPN activity levels. Despite the lack of a clear understanding of its mechanism, clozapine, an atypical antipsychotic considered the gold standard for patients with treatment-resistant schizophrenia, reduced the levels and spatiotemporal de-correlation of D1-SPN activity following amphetamine treatment. Conversely, MP-10, a once-promising antipsychotic candidate and PDE10a inhibitor, ultimately proved unsuccessful in clinical trials, was found to exacerbate the amphetamine-driven D1-SPN hyperactivity.
These findings underscore the effectiveness of in vivo single cell Ca2+ imaging of striatal circuits in discerning between treatments for schizophrenia and elucidating the mechanisms underlying their effectiveness. This new approach surpassed conventional behavioral assessments of drug efficacy and unveiled the significance of monitoring D1-SPN activity as a promising new preclinical biomarker of antipsychotic efficacy.
Jonathan Zapata, PhD, is a Lead Translational Scientist at Inscopix, where he supports preclinical research and develops research collaborations with pharmaceutical companies focusing on neuropsychiatric and neurodegenerative diseases.