Elevated synaptic PKA activity and abnormal striatal dopamine signaling in Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder
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<sup>-/-</sup> 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.
Authors
- Morgan Sheng (ORCID: https://orcid.org/0000-0002-8703-5366)
- Yang Ge (ORCID: https://orcid.org/0000-0003-3139-9053)
- D.R. Mani (ORCID: https://orcid.org/0000-0003-3914-133X)
- Zohreh Farsi (ORCID: https://orcid.org/0000-0001-7274-981X)
- Sean Simmons
- Beth A. Stevens (ORCID: https://orcid.org/0000-0003-4226-1201)
- Prabhat S. Kunwar
- Sameer Aryal (ORCID: https://orcid.org/0000-0003-3577-4383)
- Joshua Z. Levin (ORCID: https://orcid.org/0000-0002-0170-3598)
- Kevin Bonanno (ORCID: https://orcid.org/0000-0002-6712-9277)
- Alyssa Hall (ORCID: https://orcid.org/0000-0002-0609-084X)
- Deeksha Misri
- Jun Tian (ORCID: https://orcid.org/0000-0003-2371-3153)
- Steven A. Carr (ORCID: https://orcid.org/0000-0002-7203-4299)
- Bernardo L. Sabatini (ORCID: https://orcid.org/0000-0003-0095-9177)
- Hasmik Keshishian (ORCID: https://orcid.org/0000-0002-0062-9867)
- Naeem Nadaf (ORCID: https://orcid.org/0000-0002-7805-8523)
- Nader Morshed (ORCID: https://orcid.org/0000-0002-0346-9651)
- Horia Pribiag (ORCID: https://orcid.org/0000-0001-8455-1966)
- Zhanyan Fu (ORCID: https://orcid.org/0000-0001-9473-2402)
- Evan Z. Macosko (ORCID: https://orcid.org/0000-0002-2794-5165)
- Min Jee Kwon (ORCID: https://orcid.org/0000-0002-1706-0806)
- Adam Granger (ORCID: https://orcid.org/0000-0002-3953-6764)
- Nolan D. Hartley (ORCID: https://orcid.org/0000-0003-4340-3478)
- Bryan J. Song (ORCID: https://orcid.org/0000-0003-0549-4823)
- Ally Nicolella (ORCID: https://orcid.org/0000-0002-2175-6312)
- Borislav Dejanovic (ORCID: https://orcid.org/0000-0003-4191-5808)
- Bart Lodder (ORCID: https://orcid.org/0009-0001-1733-1311)
- Sahana Natarajan (ORCID: https://orcid.org/0009-0002-5975-7473)
- Nate Shepard (ORCID: https://orcid.org/0000-0002-8629-3152)
- Xiao‐Man Liu (ORCID: https://orcid.org/0000-0001-9968-3988)
- Antia Valle-Tojeiro (ORCID: https://orcid.org/0009-0004-3737-3916)
- Chuhan Geng
Institutions
- Broad Institute (US)
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- McGovern Institute for Brain Research (US)
- University Medical Center Utrecht (NL)
- Massachusetts General Hospital (US)
- Institute of Cognitive and Brain Sciences (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41467-025-66504-2
- Citations
- 2
- Primary Topic
- Neurotransmitter Receptor Influence on Behavior
- Type
- article
- Field-Weighted Citation Impact
- 1.82