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PMID: 36914641 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients.

Translational psychiatry ·Vol. 13 ·No. 1 ·2023-00-13 ·Pages 92

Herzog LE, Wang L, Yu E, Choi S, Farsi Z, Song BJ, Pan JQ, Sheng M

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.

MeSH Terms
Animals Humans Mice A Kinase Anchor Proteins/genetics Electroencephalography/methods Epilepsy Mutation Schizophrenia/genetics Sleep Receptors, N-Methyl-D-Aspartate/genetics
Chemicals
A Kinase Anchor Proteins Receptors, N-Methyl-D-Aspartate Akap11 protein, mouse
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Herzog Linnea E ORCID
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
Wang Lei
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Yu Eunah
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Choi Soonwook ORCID
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. | Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
Farsi Zohreh
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Song Bryan J
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Pan Jen Q ORCID
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Sheng Morgan ORCID
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]. | Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
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Article Info
Journal
Translational psychiatry
Abbr.
Transl Psychiatry
ISSN
2158-3188
DOI
10.1038/s41398-023-02393-7
Email
[email protected]
[email protected]
Published
2023-00-13
Epub
2023-00-13
Pages
92
Language
English
Region
United States
NLM ID
101562664
PMCID
PMC10011509
Subset
IM
Grants
NIMH NIH HHS · R01 MH115045 · United States
NIMH NIH HHS · R01 MH131719 · United States
External Links
PubMed source DOI: 10.1038/s41398-023-02393-7 PMC Full Text View journal details
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