TY  - GEN
N2  - 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.  Here, we find that GluN2A levels decline throughout adolescence in midbrain regions that contain dopamine neurons. This led us to reason that variants resulting in a loss of function of GRIN2A 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, including disrupted salience attribution and changes in 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. 
DO  - 10.6083/bpxhc43393
DO  - doi
AB  - 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.  Here, we find that GluN2A levels decline throughout adolescence in midbrain regions that contain dopamine neurons. This led us to reason that variants resulting in a loss of function of GRIN2A 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, including disrupted salience attribution and changes in 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. 
AD  - Oregon Health and Science University
T1  - Selective loss of Grin2a in adolescent dopamine neurons results in a phenotype relevant to psychosis
ED  - Moghaddam, Bita
ED  - Neve, Kim
ED  - Walker, Deena
ED  - Wolf, Marina
ED  - Williams, John
ED  - Mealer, Robert
ED  - Mentor
ED  - Committee chair
ED  - Committee member
ED  - Committee member
ED  - Committee member
ED  - Committee member
DA  - 2024-06-21
AU  - Kielhold, Michelle
L1  - https://digitalcollections.ohsu.edu/record/43393/files/Kielhold.Michelle.2024.pdf
PB  - Oregon Health and Science University
LA  - eng
PY  - 2024-06-21
ID  - 43393
L4  - https://digitalcollections.ohsu.edu/record/43393/files/Kielhold.Michelle.2024.pdf
KW  - Schizophrenia Spectrum and Other Psychotic Disorders
KW  - Disease Models, Animal
KW  - Adolescent
KW  - Dopamine
KW  - Models, Animal
KW  - psychosis
KW  - NMDA receptor
TI  - Selective loss of Grin2a in adolescent dopamine neurons results in a phenotype relevant to psychosis
Y1  - 2024-06-21
L2  - https://digitalcollections.ohsu.edu/record/43393/files/Kielhold.Michelle.2024.pdf
LK  - https://digitalcollections.ohsu.edu/record/43393/files/Kielhold.Michelle.2024.pdf
UR  - https://digitalcollections.ohsu.edu/record/43393/files/Kielhold.Michelle.2024.pdf
ER  -