TY  - JOUR
AU  - Sen, Paromita
AU  - Ortiz, Oskar
AU  - Brivio, Elena
AU  - Menegaz, Danusa
AU  - Sotillos Elliott, Laura
AU  - Du, Ying
AU  - Ries, Clemens
AU  - Chen, Alon
AU  - Wurst, Wolfgang
AU  - Lopez, Juan Pablo
AU  - Eder, Matthias
AU  - Deussing, Jan M
TI  - A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior.
JO  - Molecular psychiatry
VL  - 30
IS  - 1
SN  - 1359-4184
CY  - London
PB  - Macmillan
M1  - DZNE-2024-01431
SP  - 97 - 110
PY  - 2025
AB  - 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.
KW  - Bipolar Disorder: genetics
KW  - Bipolar Disorder: metabolism
KW  - Adenylyl Cyclases: genetics
KW  - Adenylyl Cyclases: metabolism
KW  - Animals
KW  - Mice
KW  - Mutation, Missense: genetics
KW  - Male
KW  - Humans
KW  - Mania: genetics
KW  - Polymorphism, Single Nucleotide: genetics
KW  - Disease Models, Animal
KW  - Cyclic AMP: metabolism
KW  - Hippocampus: metabolism
KW  - Mice, Inbred C57BL
KW  - Female
KW  - Adenylyl Cyclases (NLM Chemicals)
KW  - adenylyl cyclase 2 (NLM Chemicals)
KW  - Cyclic AMP (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11649569
C6  - pmid:39003412
DO  - DOI:10.1038/s41380-024-02663-w
UR  - https://pub.dzne.de/record/274003
ER  -