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| 001 | 274003 | ||
| 005 | 20250127091702.0 | ||
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| 024 | 7 | _ | |a 10.1038/s41380-024-02663-w |2 doi |
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| 024 | 7 | _ | |a 1359-4184 |2 ISSN |
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| 100 | 1 | _ | |a Sen, Paromita |0 0000-0001-9862-6914 |b 0 |
| 245 | _ | _ | |a A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior. |
| 260 | _ | _ | |a London |c 2025 |b Macmillan |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1736939100_19134 |2 PUB:(DE-HGF) |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a 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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| 650 | _ | 7 | |a Adenylyl Cyclases |0 EC 4.6.1.1 |2 NLM Chemicals |
| 650 | _ | 7 | |a adenylyl cyclase 2 |0 EC 4.6.1.1 |2 NLM Chemicals |
| 650 | _ | 7 | |a Cyclic AMP |0 E0399OZS9N |2 NLM Chemicals |
| 650 | _ | 2 | |a Bipolar Disorder: genetics |2 MeSH |
| 650 | _ | 2 | |a Bipolar Disorder: metabolism |2 MeSH |
| 650 | _ | 2 | |a Adenylyl Cyclases: genetics |2 MeSH |
| 650 | _ | 2 | |a Adenylyl Cyclases: metabolism |2 MeSH |
| 650 | _ | 2 | |a Animals |2 MeSH |
| 650 | _ | 2 | |a Mice |2 MeSH |
| 650 | _ | 2 | |a Mutation, Missense: genetics |2 MeSH |
| 650 | _ | 2 | |a Male |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Mania: genetics |2 MeSH |
| 650 | _ | 2 | |a Polymorphism, Single Nucleotide: genetics |2 MeSH |
| 650 | _ | 2 | |a Disease Models, Animal |2 MeSH |
| 650 | _ | 2 | |a Cyclic AMP: metabolism |2 MeSH |
| 650 | _ | 2 | |a Hippocampus: metabolism |2 MeSH |
| 650 | _ | 2 | |a Mice, Inbred C57BL |2 MeSH |
| 650 | _ | 2 | |a Female |2 MeSH |
| 700 | 1 | _ | |a Ortiz, Oskar |b 1 |
| 700 | 1 | _ | |a Brivio, Elena |0 0000-0002-6213-0973 |b 2 |
| 700 | 1 | _ | |a Menegaz, Danusa |b 3 |
| 700 | 1 | _ | |a Sotillos Elliott, Laura |b 4 |
| 700 | 1 | _ | |a Du, Ying |b 5 |
| 700 | 1 | _ | |a Ries, Clemens |b 6 |
| 700 | 1 | _ | |a Chen, Alon |0 0000-0003-3625-8233 |b 7 |
| 700 | 1 | _ | |a Wurst, Wolfgang |0 P:(DE-2719)2000028 |b 8 |
| 700 | 1 | _ | |a Lopez, Juan Pablo |b 9 |
| 700 | 1 | _ | |a Eder, Matthias |b 10 |
| 700 | 1 | _ | |a Deussing, Jan M |0 0000-0002-9329-5252 |b 11 |
| 773 | _ | _ | |a 10.1038/s41380-024-02663-w |g Vol. 30, no. 1, p. 97 - 110 |0 PERI:(DE-600)1502531-7 |n 1 |p 97 - 110 |t Molecular psychiatry |v 30 |y 2025 |x 1359-4184 |
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