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 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.

GRIN2A (NR2A): a gene contributing to glutamatergic involvement in schizophrenia

“…Against this backdrop, the phenotype of Grin2a +/− heterozygotes has also been examined recently, and is arguably of more relevance to schizophrenia than are the Grin2a +/− knockouts, given the protein-truncating hemizygous GRIN2A mutations and thence the presumed haploinsufficiency. Herzog and colleagues [ 54 ] used EEG to show that Grin2a +/− mice exhibit attenuated auditory steady-state responses at gamma frequencies, and increased gamma power during sleep, both features that have been observed in schizophrenia. Locomotor activity was also increased.…”

Transcriptomic and epigenomic consequences of heterozygous loss of function mutations inAKAP11, the first large-effect shared risk gene for bipolar disorder and schizophrenia

“…Genetic studies identified AKAP11 LoF as a candidate predisposing gene for both diseases. A study looking at AKAP11 mutant mice found that their EEG patterns resembled those observed in individuals with SCZ 31 . In another study, proteomic profiling of synapses found shared molecular pathway modifications between patients with SCZ, BD, and AKAP11 -mutant mouse models--mainly pathways related to ribosomes, mitochondrial respiration, and vesicle trafficking pathways 34 .…”

Enhancement of mediodorsal thalamus rescues aberrant belief dynamics in a mouse model with schizophrenia-associated mutation

“…Indeed, mice with Grin2a genetic mutations have been used as a model for schizophrenia based on this hypothesis long before the current genetic evidence. While in humans, the variations of the Grin2a gene were found in the form of point mutations in heterozygous patients, most of the behavioral phenotypes for loss of function in Grin2a were found in NR2A full knockout mice 45,46 . The robust cognitive phenotype in heterozygous Grin2a Y700X+/mice provides an opportunity to dissect neurobiological mechanisms in a system more closely modeling the genetic risks of schizophrenia.…”