Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients
Abstract Schizophrenia is a heterogeneous psychiatric disorder with a strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-03-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-023-02393-7 |
| _version_ | 1797863466479910912 |
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| author | Linnea E. Herzog Lei Wang Eunah Yu Soonwook Choi Zohreh Farsi Bryan J. Song Jen Q. Pan Morgan Sheng |
| author_facet | Linnea E. Herzog Lei Wang Eunah Yu Soonwook Choi Zohreh Farsi Bryan J. Song Jen Q. Pan Morgan Sheng |
| author_sort | Linnea E. Herzog |
| collection | DOAJ |
| description | Abstract Schizophrenia is a heterogeneous psychiatric disorder with a strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function mutations in GRIN2A (aka GluN2A or NR2A, encoding the NMDA receptor subunit 2A) and AKAP11 (A-Kinase Anchoring Protein 11). AKAP11 and GRIN2A mutations are also associated with bipolar disorder [2], and epilepsy and developmental delay/intellectual disability [1, 3, 4], respectively. Accessible in both humans and rodents, electroencephalogram (EEG) recordings offer a window into brain activity and display abnormal features in schizophrenia patients. Does loss of Grin2a or Akap11 in mice also result in EEG abnormalities? We monitored EEG in heterozygous and homozygous knockout Grin2a and Akap11 mutant mice compared with their wild-type littermates, at 3- and 6-months of age, across the sleep/wake cycle and during auditory stimulation protocols. Grin2a and Akap11 mutants exhibited increased resting gamma power, attenuated auditory steady-state responses (ASSR) at gamma frequencies, and reduced responses to unexpected auditory stimuli during mismatch negativity (MMN) tests. Sleep spindle density was reduced in a gene dose-dependent manner in Akap11 mutants, whereas Grin2a mutants showed increased sleep spindle density. The EEG phenotypes of Grin2a and Akap11 mutant mice show a variety of abnormal features that overlap considerably with human schizophrenia patients, reflecting systems-level changes caused by Grin2a and Akap11 deficiency. These neurophysiologic findings further substantiate Grin2a and Akap11 mutants as genetic models of schizophrenia and identify potential biomarkers for stratification of schizophrenia patients. |
| first_indexed | 2024-04-09T22:36:02Z |
| format | Article |
| id | doaj.art-6ef43cb727fa46878a20e353d3dbdbe9 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-04-09T22:36:02Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-6ef43cb727fa46878a20e353d3dbdbe92023-03-22T12:27:08ZengNature Publishing GroupTranslational Psychiatry2158-31882023-03-0113111110.1038/s41398-023-02393-7Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patientsLinnea E. Herzog0Lei Wang1Eunah Yu2Soonwook Choi3Zohreh Farsi4Bryan J. Song5Jen Q. Pan6Morgan Sheng7Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardStanley Center for Psychiatric Research, Broad Institute of MIT and HarvardStanley Center for Psychiatric Research, Broad Institute of MIT and HarvardStanley Center for Psychiatric Research, Broad Institute of MIT and HarvardStanley Center for Psychiatric Research, Broad Institute of MIT and HarvardStanley Center for Psychiatric Research, Broad Institute of MIT and HarvardStanley Center for Psychiatric Research, Broad Institute of MIT and HarvardStanley Center for Psychiatric Research, Broad Institute of MIT and HarvardAbstract Schizophrenia is a heterogeneous psychiatric disorder with a strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function mutations in GRIN2A (aka GluN2A or NR2A, encoding the NMDA receptor subunit 2A) and AKAP11 (A-Kinase Anchoring Protein 11). AKAP11 and GRIN2A mutations are also associated with bipolar disorder [2], and epilepsy and developmental delay/intellectual disability [1, 3, 4], respectively. Accessible in both humans and rodents, electroencephalogram (EEG) recordings offer a window into brain activity and display abnormal features in schizophrenia patients. Does loss of Grin2a or Akap11 in mice also result in EEG abnormalities? We monitored EEG in heterozygous and homozygous knockout Grin2a and Akap11 mutant mice compared with their wild-type littermates, at 3- and 6-months of age, across the sleep/wake cycle and during auditory stimulation protocols. Grin2a and Akap11 mutants exhibited increased resting gamma power, attenuated auditory steady-state responses (ASSR) at gamma frequencies, and reduced responses to unexpected auditory stimuli during mismatch negativity (MMN) tests. Sleep spindle density was reduced in a gene dose-dependent manner in Akap11 mutants, whereas Grin2a mutants showed increased sleep spindle density. The EEG phenotypes of Grin2a and Akap11 mutant mice show a variety of abnormal features that overlap considerably with human schizophrenia patients, reflecting systems-level changes caused by Grin2a and Akap11 deficiency. These neurophysiologic findings further substantiate Grin2a and Akap11 mutants as genetic models of schizophrenia and identify potential biomarkers for stratification of schizophrenia patients.https://doi.org/10.1038/s41398-023-02393-7 |
| spellingShingle | Linnea E. Herzog Lei Wang Eunah Yu Soonwook Choi Zohreh Farsi Bryan J. Song Jen Q. Pan Morgan Sheng Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients Translational Psychiatry |
| title | Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients |
| title_full | Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients |
| title_fullStr | Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients |
| title_full_unstemmed | Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients |
| title_short | Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients |
| title_sort | mouse mutants in schizophrenia risk genes grin2a and akap11 show eeg abnormalities in common with schizophrenia patients |
| url | https://doi.org/10.1038/s41398-023-02393-7 |
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