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Sen, P.* ; Ortiz, O. ; Brivio, E.* ; Menegaz, D.* ; Sotillos Elliott, L.* ; Du, Y.* ; Ries, C.* ; Chen, A.* ; Wurst, W. ; Lopez, J.P.* ; Eder, M.* ; Deussing, J.M.*

A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior.

Mol. Psychiatry, DOI: 10.1038/s41380-024-02663-w (2024)
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The single nucleotide polymorphism rs13166360, causing a substitution of valine (Val) 147 to leucine (Leu) in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3',5'-cylic adenosine monophosphate (cAMP) by altering its subcellular localization. We established mice specifically carrying the Val to Leu substitution using CRISPR/Cas9-based gene editing. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Mutant animals show additional characteristic signs of rodent mania models, i.e., they are hypersensitive to amphetamine, the observed mania-like behaviors are responsive to lithium treatment and the Val to Leu substitution results in a shifted excitatory/inhibitory synaptic balance towards more excitation. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which is reminiscent of the alternations characterizing the symptomatology in BD patients. Single-cell RNA-seq (scRNA-seq) revealed widespread Adcy2 mRNA expression in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as a BD risk gene, provide insights into underlying disease mechanisms, and potentially open novel avenues for therapeutic intervention strategies.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Long-term-memory; Susceptibility; Mouse; Gene; Stress; Rat; Identification; Substitution; Dysfunction
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 1359-4184
e-ISSN 1476-5578
Journal Molecular Psychiatry
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500500-001
Grants German Ministry of Science and Education (IntegraMent: Integrated Understanding of Causes and Mechanisms in Mental Disorders)
Max Planck Society (JMD)
Bundesministerium fr Bildung und Forschung (Federal Ministry of Education and Research)
DOI 10.1038/s41380-024-02663-w
WOS ID 001266976500001
Scopus ID 85198488643
PubMed ID 39003412
Erfassungsdatum 2024-07-15
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