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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Rare protein-truncating variants (PTVs) in AKAP11 are linked to schizophrenia risk.
• Previous studies noted EEG and synaptic proteome alterations in Akap11 mutant mice.
• Synaptic dysfunction is hypothesized to contribute to AKAP11 deficiency in schizophrenia pathogenesis.

Purpose of the Study:

• To investigate the impact of Akap11 deficiency on schizophrenia-relevant phenotypes.
• To elucidate the role of Akap11 in synaptic function and behavior.

Main Methods:

• Generated Akap11 knockout mice for study.
• Conducted behavioral evaluations, neuronal sparse labeling, and electron microscopy.
• Utilized immunoprecipitation mass spectrometry (IP-MS) to identify Akap11 interaction proteins.

Main Results:

• Akap11 deficient mice showed impaired prepulse inhibition and anxiety-like behaviors.
• Reduced spine density and altered synaptogenesis (synapses, vesicles, PSD length) were observed.
• Identified 222 Akap11 interacting proteins, including synaptic and actin-related proteins, suggesting roles in RNA splicing, cell organization, and signaling pathways.

Conclusions:

• Akap11 deficiency leads to synaptic and behavioral deficits in mice.
• These findings support AKAP11's significance as a schizophrenia risk gene.
• The study provides insights into the mechanisms linking AKAP11 to schizophrenia pathogenesis.