Exploring Genetic Models in Schizophrenia Research: A Teaser From ACNP Annual Meeting

Sharing his thoughts at the 63rd Annual Meeting of the American College of Neuropsychopharmacology, Thomas R. Kosten, MD, member of the Psychiatric Times editorial board, discussed research on the genetic underpinnings of schizophrenia. He was particularly intrigued by a presentation from Zohreh Farsi, PhD, group leader at the Broad Institute of MIT and Harvard, who developed a rodent model based on the GRIN2a genetic polymorphism.¹

“It’s surprising that a single gene could even imitate anything about schizophrenia,” Kosten remarked, noting the model’s effectiveness in mimicking key aspects of the disorder. In the presentation, Farsi explained that loss of even a single copy of GRIN2a in mice has such large effects on the brain transcriptome and synapse proteome that it can mimic hyperactivity, hypersensitivity to amphetamine, elevated gamma oscillation power on EEG recordings, as well as differential effects on activity of prefrontal cortex, hippocampus and striatum—all of which mimic schizophrenia in humans.

Farsi et al treated mice with haloperidol, clozapine, and xanomeline (the active ingredient in the newly approved antipsychotic Cobenfy) to determine if any could ameliorate the effects of the loss. Indeed, the drugs had some effects, including partially reversing abnormal behavioral patterns and reversal of transcriptomic changes in the brain. Farsi and colleagues determined their data validated the GRIN2a+/- mice as an animal model for studying schizophrenia.

“There was some very, very persuasive data... that will probably lead to a variety of agents targeting that particular gene,” Kosten said, adding these advances could pave the way for novel treatments with fewer side effects than current options like clozapine or haloperidol. Innovative work like this presentation underscores ACNP’s commitment to translational research, moving discoveries “from one stage of animals and models to the real thing,” Kosten said.

Reference

1. Farsi Z. Grin2a Mutant Mouse, a Genetic Schizophrenia Mouse Model with Utility for Testing Novel Therapeutics. Presented at the 63rd Annual Meeting of the American College of Neuropsychopharmacology. Phoenix, AZ; December 8 – 12, 2024.