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Elevated synaptic PKA activity and abnormal striatal dopamine signaling in Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder

Author

Listed:
  • Bryan J. Song

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Yang Ge

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Ally Nicolella

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Min Jee Kwon

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Bart Lodder

    (Harvard Medical School, Department of Neurobiology, Howard Hughes Medical Institute
    University Medical Center Utrecht and University Utrecht, Brain Center, Department of Translational Neuroscience)

  • Kevin Bonanno

    (The Broad Institute of MIT and Harvard, The Proteomics Platform)

  • Antia Valle-Tojeiro

    (The Broad Institute of MIT and Harvard, The Proteomics Platform)

  • Nolan D. Hartley

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research
    Massachusetts Institute of Technology, Yang Tan Collective and McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences)

  • Kira Perzel Mandell

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • John Adeleye

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Deeksha Misri

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Chuhan Geng

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Sahana Natarajan

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Inès Picard

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Nate Shepard

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Alyssa Hall

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Jiawen Tian

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research
    Massachusetts Institute of Technology, Yang Tan Collective and McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences)

  • Sameer Aryal

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Zohreh Farsi

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Xiao-Man Liu

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Nader Morshed

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research
    Massachusetts Institute of Technology, Yang Tan Collective and McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences)

  • Naeem M. Nadaf

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Horia Pribiag

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Sean K. Simmons

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • D. R. Mani

    (The Broad Institute of MIT and Harvard, The Proteomics Platform)

  • Beth Stevens

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research
    Boston Children’s Hospital, F.M. Kirby Neurobiology Center
    Boston Children’s Hospital, Howard Hughes Medical Institute)

  • Prabhat S. Kunwar

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Zhanyan Fu

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research
    Massachusetts Institute of Technology, Yang Tan Collective and McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences)

  • Evan Z. Macosko

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research
    Department of Psychiatry, Massachusetts General Hospital)

  • Joshua Z. Levin

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Bernardo L. Sabatini

    (Harvard Medical School, Department of Neurobiology, Howard Hughes Medical Institute)

  • Steven A. Carr

    (The Broad Institute of MIT and Harvard, The Proteomics Platform)

  • Borislav Dejanovic

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research
    Vigil Neuroscience)

  • Hasmik Keshishian

    (The Broad Institute of MIT and Harvard, The Proteomics Platform)

  • Adam J. Granger

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research)

  • Morgan Sheng

    (The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research
    Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences)

Abstract

Loss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. To determine the neurobiological functions of AKAP11, we conduct multi-omic and neurobiological analyses of Akap11 mutant mouse brains. We find that AKAP11 is a key regulator of PKA proteostasis in the brain whose loss leads to dramatically increased levels of PKA subunits and phosphorylated PKA substrates, especially in synapses. Akap11 mutant mice show extensive transcriptomic changes throughout the brain, including prominent decreases in synapse-related genes sets. Gene expression is highly impacted in spiny projection neurons of the striatum, a brain region implicated in motivation, cognition and psychotic disorders. Real-time measurements of PKA activity reveal elevated basal PKA activity in the striatum of Akap11-/- mice, with exaggerated additional response to dopamine receptor antagonists. Behaviorally, Akap11 mutant mice show abnormally prolonged locomotor response to amphetamine, deficits in associative learning and contextual discrimination, as well as depression-like behaviors. Our study connects molecular changes to circuit dysfunction and behavioral disturbance in a genetically valid animal model of psychotic disorder.

Suggested Citation

  • Bryan J. Song & Yang Ge & Ally Nicolella & Min Jee Kwon & Bart Lodder & Kevin Bonanno & Antia Valle-Tojeiro & Nolan D. Hartley & Kira Perzel Mandell & John Adeleye & Deeksha Misri & Chuhan Geng & Saha, 2025. "Elevated synaptic PKA activity and abnormal striatal dopamine signaling in Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder," Nature Communications, Nature, vol. 16(1), pages 1-25, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-66504-2
    DOI: 10.1038/s41467-025-66504-2
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