Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The single nucleotide polymorphism rs, causing a substitution of valine Val to leucine Leu in the adenylyl cyclase 2 ADCY2has previously been associated with bipolar disorder BD. 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. 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. Bipolar disorder BD collectively terms a group of chronic psychiatric disorders characterized by recurrent manic and depressive episodes. This group of mental disorders is accompanied by severely impaired psychosocial functioning and premature mortality [ 2 ]. Genome-wide association studies GWAS have identified numerous loci associated with BD over the past years [ 678910111213 ]. Among these loci, the adenylyl cyclase 2 gene ADCY2 has been identified as a potential risk gene for BD [ 14 ], a finding which has been replicated by the latest, and to date largest, BD GWAS meta-analyses [ 1516 ]. Their activity is controlled by heteromeric G proteins. Thereby, these enzymes are dating someone with manic depression of integrating signals from various G protein-coupled receptors GPCRs which are conveyed onto downstream signaling pathways via the second messenger cAMP [ 17 ]. The family of mammalian membrane-bound ADCYs comprises 9 isoforms, which are classified according to their signaling properties. Similar to all other ADCYs, ADCY2 is expressed in the central nervous system but displays a distinct and broader expression pattern compared to other group II ADCYs [ 18 ]. In the past decades, psychiatric research has particularly focused on neurotransmitter- and neuromodulator-related GPCRs as potential risk factors and drug targets for therapeutic intervention [ 1920 ]. In contrast, ADCYs, which are essential for the generation of the second messenger cAMP, have largely been ignored [ 21 ]. This is somewhat surprising as accumulating evidence from human [ 14222324 ] and mouse [ 252627282930 ] studies suggests an involvement of different ADCYs dating someone with manic depression psychiatric disorders including autism, schizophrenia, depression and BD. In contrast to the vast majority of disease-associated SNPs, which are intergenic or intronic, one of the BD-associated SNPs - rs - is located in the 3 rd exon of the ADCY2 gene Fig. Hence, it encodes a missense mutation resulting in a Val to Leu substitution at position ValLeu within the 4 th transmembrane helix of the first transmembrane domain Fig. Among ADCYs, this missense mutation is unique and its functional consequences are unclear. In ADCY2 homologs of different species, Val is fully conserved. Among other family members, however, it is only found in its closest relative ADCY7 Fig. Each dot represents an individual cell. Here we investigated the direct consequences of rs on ADCY2 function in vitro and in vivo. To validate ADCY2 as a potential BD risk gene, we used heterologous expression to study protein function and generated a transgenic mouse model carrying the Val to Leu substitution. The latter approach allowed us to interrogate effects of the missense mutation with regards to BD-related endophenotypes and to probe its potential interaction with chronic stress as an environmental risk factor. Finally, we unraveled how the presence of the disease-associated SNP altered the transcriptional landscape in the ventral hippocampus, a brain structure involved in the regulation of emotionality and BD-related behavioral phenotypes. Expression vectors pcDNA3. Protein expression was assessed by Western blot and immunofluorescence. For details, refer to online Supplementary Information. Cell lines, originally purchased from the American Type Culture Collection, are regularly tested for mycoplasma contamination using PCR test. All animal experiments were conducted with the approval of and in accordance with the Guide of the Care and Use of Laboratory Animals of the Government of Upper Bavaria, Germany Az. All experiments were conducted with adult male mice age: 2—5 months. The ssODN contained 2 silent mutations, one that added a restriction enzyme site Alu I for genotyping purposes and another one that obliterated the PAM sequence NGG so that the donor DNA was not cleaved by Cas9 Fig. A heterozygous founder carrying the Leu mutation was used to establish the Adcy2 VL line.
Bipolar affective disorder, which oscillates between the two poles of mood Latin: bipolar of great depression and exaggerated euphoria, is relatively common in the adult population, affecting around one percent. A genome-wide association study implicates diacylglycerol kinase eta DGKH and several other genes in the etiology of bipolar disorder. Recording, tracking and scoring of animal behaviors was carried out using the automated video tracking system ANY-maze ANY-maze 6. Local Network for the Treatment of Heart Attack Transregional Network for Stroke Intervention with Telemedicine TRANSIT Stroke Level-1 Shock Trauma Center University Hospital of Würzburg. In the control group, L mice showed again signs of mania-like behavior as indicated by increased time spent in the center and an increased number of entries to the center of the OFT. Shahoha M, Cohen R, Ben-Simon Y, Ashery U.
Introduction
Objective: Research in adults has identified an association between bipolar disorder and suicidal behavior. It is argued that among studies that were published within recent decades to this. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which. Compares development within the fields of medical genetics and psychiatry. This relationship, however. Bipolar affective disorder is a serious mood disorder characterized by manic and depressive mood swings.Animal models of bipolar mania: The past, present and future. Statistical analyses were performed using the commercially available software GraphPad Prism v5. The latter switched from a manic to a depressive-like state as indicated by increased anxiety-related behavior in the OFT and DaLi. Effects on adenylate cyclase activity and beta-adrenergic receptor binding in normal subjects. LSE performed cell culture experiments. Correspondence to Jan M. Logan RW, McClung CA. In the forced swim test FST , L mice showed more active stress-coping behavior compared to WT littermates as indicated by decreased floating and increased swimming Fig. Article PubMed CAS Google Scholar Wong ST, Athos J, Figueroa XA, Pineda VV, Schaefer ML, Chavkin CC, et al. Vieta E, Berk M, Schulze TG, Carvalho AF, Suppes T, Calabrese JR, et al. Further information You can find more information on bipolar disorder on the German Society for Bipolar Disorders DGBS website , in our flyer and in a short film showcasing bipolar disorders in German. Article PubMed PubMed Central Google Scholar Gordovez FJA, McMahon FJ. Article PubMed CAS Google Scholar Bollen E, Puzzo D, Rutten K, Privitera L, De Vry J, Vanmierlo T, et al. In sum, the scRNA-seq analysis provides valuable entry points for a mechanistic understanding of alterations induced by the BD-associated ADCY2 variant which merit closer inspection in future studies. Mol Psychiatry 30 , 97— Dienes KA, Hammen C, Henry RM, Cohen AN, Daley SE. Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation. Genome-wide association study of more than 40, bipolar disorder cases provides new insights into the underlying biology. This mutation, which is located in the 7 th transmembrane helix of the M2 domain, also attenuates enzyme activity [ 45 ]. Sie müssen JavaScript in Ihrem Browser aktivieren um alle Funktionen der Seite nutzen zu können. CR performed immunostainings and quantified synaptic markers. In ADCY2 homologs of different species, Val is fully conserved. Similarly, exposure to CSDS entailed clear signs of social-avoidance behavior Fig. Wallis And Futuna Western Sahara Yemen Zambia Zimbabwe. Biol Psychiatry. Article PubMed PubMed Central CAS Google Scholar Dedic N, Pohlmann ML, Richter JS, Mehta D, Czamara D, Metzger MW, et al. The second speaker will be the Canadian filmmaker Kalina Bertin. Therefore, we assessed whether the mania-like state presented by homozygous mutant Adcy2 VL mice could be reversed by lithium treatment. Masana MI, Bitran JA, Hsiao JK, Mefford IN, Potter WZ. Thank you for visiting nature. Similar to all other ADCYs, ADCY2 is expressed in the central nervous system but displays a distinct and broader expression pattern compared to other group II ADCYs [ 18 ]. Ostrom RS, Bogard AS, Gros R, Feldman RD. Scientific Education. Lopez JP, Lucken MD, Brivio E, Karamihalev S, Kos A, De Donno C, et al. Article PubMed CAS Google Scholar Green EK, Hamshere M, Forty L, Gordon-Smith K, Fraser C, Russell E, et al.
