000043393 001__ 43393 000043393 005__ 20240615125004.0 000043393 0247_ $$2doi$$a10.6083/bpxhc43393 000043393 037__ $$aETD 000043393 041__ $$aeng 000043393 245__ $$aSelective loss of Grin2a in adolescent dopamine neurons results in a phenotype relevant to psychosis 000043393 260__ $$bOregon Health and Science University 000043393 269__ $$a2024-06-21 000043393 336__ $$aDissertation 000043393 502__ $$bPh.D. 000043393 502__ $$gBehavioral & Systems Neuroscience 000043393 520__ $$aPsychosis is a hallmark of schizophrenia. It typically emerges in late adolescence and is associated with striatal dopamine abnormalities. Most genes implicated in the risk for schizophrenia involve ubiquitous targets that do not explain the latent expression of psychosis or dopaminergic disruptions. Here, we describe an etiologically relevant mechanism for adolescent onset of dopamine abnormalities and psychosis. We focused on GRIN2A, which encodes the GluN2A subunit of the NMDA receptor. Both common variants in this gene as well as rare missense and protein-truncating variants were recently identified as genetic risk factors for schizophrenia. Here, we find that GluN2A levels decline throughout adolescence in midbrain regions that contain dopamine neurons. This led us to reason that variants resulting in a loss of function of GRIN2A could augment this natural adolescent developmental process and contribute to the emergence of psychosis at this age. Consistent with this mechanism, virally mediated Grin2a knockout in rat adolescent dopamine neurons resulted in a phenotype mirroring psychosis, including disrupted salience attribution and changes in dopamine release during prediction error signaling. Overall, these data provide mechanistic insight into how variants of GRIN2A may lead to the latent presentation of psychosis and abnormalities in dopamine dynamics in schizophrenia. Our approach provides a model with construct and face validity to aid future discovery of course altering treatments for schizophrenia. 000043393 536__ $$oNIMH$$cR01MH115027-04 000043393 536__ $$oNIMH$$cR01MH048404-29 000043393 540__ $$fCC BY 000043393 542__ $$fIn copyright - single owner 000043393 650__ $$aSchizophrenia Spectrum and Other Psychotic Disorders$$032030 000043393 650__ $$aDisease Models, Animal$$017932 000043393 650__ $$aAdolescent$$014285 000043393 650__ $$aDopamine$$018026 000043393 650__ $$aModels, Animal$$033025 000043393 6531_ $$apsychosis 000043393 6531_ $$aNMDA receptor 000043393 691__ $$aSchool of Medicine$$041369 000043393 692__ $$aDepartment of Behavioral Neuroscience$$041394 000043393 7001_ $$aKielhold, Michelle$$uOregon Health and Science University$$041354$$10000-0002-9304-9174 000043393 7201_ $$aMoghaddam, Bita$$uOregon Health and Science University$$041354$$eMentor$$7Personal 000043393 7201_ $$aNeve, Kim$$uOregon Health and Science University$$041354$$eCommittee chair$$7Personal 000043393 7201_ $$aWalker, Deena$$uOregon Health and Science University$$041354$$eCommittee member$$7Personal 000043393 7201_ $$aWolf, Marina$$uOregon Health and Science University$$041354$$eCommittee member$$7Personal 000043393 7201_ $$aWilliams, John$$uOregon Health and Science University$$041354$$eCommittee member$$7Personal 000043393 7201_ $$aMealer, Robert$$uOregon Health and Science University$$041354$$eCommittee member$$7Personal 000043393 8564_ $$9dd30ec30-6251-4bf0-af44-7c4f76630ffd$$s3002982$$uhttps://digitalcollections.ohsu.edu/record/43393/files/Kielhold.Michelle.2024.pdf 000043393 909CO $$ooai:digitalcollections.ohsu.edu:43393$$pstudent-work 000043393 980__ $$aTheses and Dissertations 000043393 981__ $$aPublished$$b2024-06-14