PhD seminar – Bita Moghaddam

Name: PhD seminar – Bita Moghaddam
Start: 2025-02-07T11:30:00+01:00
End: 2025-02-07T11:30:00+01:00

vendredi 7 février / 11:30

Venue: Centre Broca

In the frame of the Girls and Women of Science Day

Bita Moghaddam
Ruth Matarazzo Professor of Behavioral Neuroscience
Professor of Psychiatry
Oregon Health and Science University, USA
Lab website https://www.moghaddamlab.org/
https://en.wikipedia.org/wiki/Bita_Moghaddam

Title

Evolution of the Glutamate Models of Psychosis

Abstract

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.