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000274003 245__ $$aA bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior.
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000274003 520__ $$aThe 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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000274003 650_7 $$0EC 4.6.1.1$$2NLM Chemicals$$aAdenylyl Cyclases
000274003 650_7 $$0EC 4.6.1.1$$2NLM Chemicals$$aadenylyl cyclase 2
000274003 650_7 $$0E0399OZS9N$$2NLM Chemicals$$aCyclic AMP
000274003 650_2 $$2MeSH$$aBipolar Disorder: genetics
000274003 650_2 $$2MeSH$$aBipolar Disorder: metabolism
000274003 650_2 $$2MeSH$$aAdenylyl Cyclases: genetics
000274003 650_2 $$2MeSH$$aAdenylyl Cyclases: metabolism
000274003 650_2 $$2MeSH$$aAnimals
000274003 650_2 $$2MeSH$$aMice
000274003 650_2 $$2MeSH$$aMutation, Missense: genetics
000274003 650_2 $$2MeSH$$aMale
000274003 650_2 $$2MeSH$$aHumans
000274003 650_2 $$2MeSH$$aMania: genetics
000274003 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide: genetics
000274003 650_2 $$2MeSH$$aDisease Models, Animal
000274003 650_2 $$2MeSH$$aCyclic AMP: metabolism
000274003 650_2 $$2MeSH$$aHippocampus: metabolism
000274003 650_2 $$2MeSH$$aMice, Inbred C57BL
000274003 650_2 $$2MeSH$$aFemale
000274003 7001_ $$aOrtiz, Oskar$$b1
000274003 7001_ $$00000-0002-6213-0973$$aBrivio, Elena$$b2
000274003 7001_ $$aMenegaz, Danusa$$b3
000274003 7001_ $$aSotillos Elliott, Laura$$b4
000274003 7001_ $$aDu, Ying$$b5
000274003 7001_ $$aRies, Clemens$$b6
000274003 7001_ $$00000-0003-3625-8233$$aChen, Alon$$b7
000274003 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b8
000274003 7001_ $$aLopez, Juan Pablo$$b9
000274003 7001_ $$aEder, Matthias$$b10
000274003 7001_ $$00000-0002-9329-5252$$aDeussing, Jan M$$b11
000274003 773__ $$0PERI:(DE-600)1502531-7$$a10.1038/s41380-024-02663-w$$gVol. 30, no. 1, p. 97 - 110$$n1$$p97 - 110$$tMolecular psychiatry$$v30$$x1359-4184$$y2025
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