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

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, Sahana Natarajan, Inès Picard, Nate Shepard, Alyssa Hall, Jiawen Tian, Sameer Aryal, Zohreh Farsi, Xiao-Man Liu, Nader Morshed, Naeem M. Nadaf, Horia Pribiag, Sean K. Simmons, D. R. Mani, Beth Stevens, Prabhat S. Kunwar, Zhanyan Fu, Evan Z. Macosko, Joshua Z. Levin, Bernardo L. Sabatini, Steven A. Carr, Borislav Dejanovic, Hasmik Keshishian, Adam J. Granger () and Morgan Sheng ()
Additional contact information
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
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
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
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
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
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
Evan Z. Macosko: The Broad Institute of MIT and Harvard, The Stanley Center for Psychiatric Research
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
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

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-66504-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-66504-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-66504-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().