Journal Article

Schizophrenia-Related Synaptic Dysfunction and Abnormal Sensorimotor Gating in Akap11-Deficient Mice

Li, Ming, Yin, Mei-Yu, Chang, Hong, Xiao, Xiao, Guo, Yingqi, Wang, Lu, Li, Cong, Zhang, Ya-Qi, Cai, Xin, Zhang, Qing, Ma, Guolan, Li, Shi-Wu

2026

Overview

Abstract Background and Hypothesis Large-scale whole exome sequencing (WES) analyses have implicated rare protein-truncating variants (PTVs) in the AKAP11 gene contributing to schizophrenia risk. Previous studies reported alterations of EEG characteristics and synaptic proteome in Akap11 mutant mice. We hypothesize that synaptic dysfunction contributes to AKAP11 deficiency in the pathogenesis of schizophrenia. Study Design We generated an Akap11 knockout mouse and employed a series of behavioral evaluations, neuronal sparse labeling assays, electron microscopy, and immunoprecipitation mass spectrometry (IP-MS) to elucidate the impacts of Akap11 on schizophrenia-relevant phenotypes. Study Results Our behavioral paradigm evaluations revealed that Akap11 deficient mice exhibited impaired prepulse inhibition and anxiety-like behaviors compared with their wild-type littermates. Neuronal sparse labeling assays indicated a significant reduction in the density of total and thin spines in Akap11 deficient mice, and ultrastructural analysis via electron microscopy disclosed marked alterations in synaptogenesis after suppressing Akap11, including the reduced density of typical synapses, synaptic vesicle density, and postsynaptic density (PSD) length. IP-MS identified 222 high-confidence interaction proteins of Akap11, encompassing synapses-related proteins (eg, Exoc4, Ncam1, Picalm, Vapb) and actin-related proteins (Actb, Diaph1), and enrichment analyses further showed that Akap11 may contribute to RNA splicing, extracellular matrix organization, axon guidance, post-NMDA receptor activation events, GPER1 signaling and PKA activation pathways. Conclusions Together, these findings delineated the synaptic and behavioral phenotypes in Akap11 deficient mice, shedding light on the potential mechanisms underlying the role of rare PTVs in schizophrenia and substantiating the significance of AKAP11 as a risk gene for this illness.

• Publisher: Oxford University Press
• Subject: A Kinase Anchor Proteins - deficiency / A Kinase Anchor Proteins - genetics / Animals / Anxiety - physiopathology / Behavior, Animal - physiology / Disease Models, Animal / Male / Mice / Mice, Knockout / Microscopy / Prepulse Inhibition - physiology / Proteins / Regular / Schizophrenia / Schizophrenia - genetics / Schizophrenia - metabolism / Schizophrenia - physiopathology / Sensory Gating - physiology / Synapses - metabolism / Synapses - pathology / Synapses - ultrastructure