Evolution of the Glutamate Models of Psychosis
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Bita Moghaddam, Ph.D.
Professor of Behavioral Neuroscience, School of Medicine
Behavioral Neuroscience Graduate Program, School of Medicine
Oregon Health & Science University
Bita Moghaddam is Ruth Matarazzo Professor in Behavioral Neuroscience at OHSU and author of KETAMINE. She received a PhD in Biochemistry from the University of Kansas and postdoctoral training in pharmacology at Yale University. She joined the faculty of the Department of Psychiatry at Yale University in 1990 where she quickly rose to the rank of full professor. In 2003 she moved to the University of Pittsburgh as professor of Neuroscience and Psychiatry. She joined OHSU in 2017. Her research, which has been supported continuesly by focuses on understanding the neuronal basis of complex behaviors that are critical to mental health, and is distinguished by the substantial impact on the field (H-index 81, overall citations ~ 25,000).
Summary
Psychosis is a hallmark of schizophrenia. It typically emerges in late adolescence and is associated with striatal dopamine abnormalities. Most genes implicated in the risk for schizophrenia involve ubiquitous targets that do not explain the latent expression of psychosis or dopaminergic disruptions. Here, we describe an etiologically relevant mechanism for adolescent onset of dopamine abnormalities and psychosis. We focused on GRIN2A, which encodes the GluN2A subunit of the NMDA receptor. Both common variants in this gene as well as rare missense and protein-truncating variants were recently identified as genetic risk factors for schizophrenia. We find that GluN2A levels decline throughout adolescence in midbrain regions that contain dopamine neurons. This led us to reason that variants that reduce GRIN2A function could augment this natural adolescent developmental process and contribute to the emergence of psychosis at this age. Consistent with this mechanism, virally mediated Grin2a knockout in rat adolescent dopamine neurons resulted in a phenotype mirroring psychosis. These included disruptions in salience attribution and dopamine release during prediction error signaling. Overall, these data provide mechanistic insight into how variants of GRIN2A may lead to the latent presentation of psychosis and abnormalities in dopamine dynamics in schizophrenia. Our approach provides a model with construct and face validity to aid future discovery of course altering treatments for schizophrenia.
Learning Objectives:
- Understand the rationale for using etiologically relevant animal models relevant to schizophrenia: Explore why animal models are necessary for studying complex genetic and developmental aspects of schizophrenia
- Discuss genetic manipulation techniques and design of behavioral phenotypes: Explore techniques to study specific genes at specific developmental timepoints that allow for behavioral phenotyping relevant to psychosis
- Consider therapeutic implications and future research directions: Identify innovative experimental approaches that can help develop course-altering treatments for schizophrenia
https://videocast.nih.gov/watch=55016
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