Journal Article

DZNE-2024-01431

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior.

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

2025
Macmillan London

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Please use a persistent id in citations: doi:10.1038/s41380-024-02663-w

Abstract: 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.

Keyword(s): Bipolar Disorder: genetics (MeSH) ; Bipolar Disorder: metabolism (MeSH) ; Adenylyl Cyclases: genetics (MeSH) ; Adenylyl Cyclases: metabolism (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Mutation, Missense: genetics (MeSH) ; Male (MeSH) ; Humans (MeSH) ; Mania: genetics (MeSH) ; Polymorphism, Single Nucleotide: genetics (MeSH) ; Disease Models, Animal (MeSH) ; Cyclic AMP: metabolism (MeSH) ; Hippocampus: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Female (MeSH) ; Adenylyl Cyclases ; adenylyl cyclase 2 ; Cyclic AMP

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Contributing Institute(s):

1. Genome Engineering (AG Wurst)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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