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 bipolar disorder and dating Val to leucine Leu in the adenylyl cyclase 2 ADCY2has previously been associated with bipolar disorder Bipolar disorder and dating. 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 bipolar disorder and dating 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 capable 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 in 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 Bipolar disorder and dating 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. Potential off-target sites were identified using CRISPRscan and Cas-OFFinder allowing up to 2 mismatches [ 3233 ]. Highlighted are the Alu I restriction site and the ValLeu substitution present in L mice. The chronic social defeat was performed as previously described [ 34 ].
Among other family members, however, it is only found in its closest relative ADCY7 Fig. Mol Psychiatry. This suggests that inflammation may play a role in the development of the illness. Article PubMed PubMed Central CAS Google Scholar Koenders MA, Giltay EJ, Spijker AT, Hoencamp E, Spinhoven P, Elzinga BM. 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.
Materials and methods
meter und IRI-Ska-. Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3',5'-cylic. Whether you have bipolar disorder or are dating someone with the condition, learn what you can do to maintain a healthy and fulfilling. We investigated the relationship between personality profiles and the prediction of longterm illness severity in patients with bipolar disorder (BD). PDF | Deficits of theory of mind and empathy have been reported in bipolar disorder and schizophrenia Daten, MASC-Para-.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. Download PDF. Cas-OFFinder: a fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA-guided endonucleases. Griebel G, Holsboer F. Brain Res. Hypomania is a milder form of mania, but it can still cause significant problems in social, professional and personal relationships. Animals were allocated to the experimental groups in a semi-randomized manner and data analysis was performed blinded to the group allocation. In particular in the first two dark phases, L mice showed significantly higher activity compared to WT littermates Fig. Internationale Co-Autor:innen. Angaben zur Forschungsförderung. Curr Biol. Chair of Developmental Genetics, Munich School of Life Sciences Weihenstephan, Technical University of Munich, , Freising, Germany. Between these phases, people with the disorder are completely healthy. The most common model of BD involves psychostimulant-induced hyperlocomotion. To be able to offer low-threshold help, we offer telephone consultation hours every Thursday from 3pm to 5pm. Tibbs ZE, Guidry AL, Falany JL, Kadlubar SA, Falany CN. Article PubMed CAS Google Scholar Lee Y, Zhang Y, Kim S, Han K. Homozygous mutant L mice did not show any gross abnormalities. Thank you for visiting nature. Characterization of Disease-Associated Mutations in Human Transmembrane Proteins. Mol Psychiatry 30 , 97— Since the difference in activity could not be attributed to different levels of protein expression or turnover, we hypothesized alterations in ADCY2 localization or trafficking. Here we investigated the direct consequences of rs on ADCY2 function in vitro and in vivo. This group of mental disorders is accompanied by severely impaired psychosocial functioning and premature mortality [ 2 ]. ISSN Article PubMed CAS Google Scholar Molnar J, Szakacs G, Tusnady GE. Article PubMed PubMed Central CAS Google Scholar Ostrom KF, LaVigne JE, Brust TF, Seifert R, Dessauer CW, Watts VJ, et al. Bipolar disorder BD collectively terms a group of chronic psychiatric disorders characterized by recurrent manic and depressive episodes. Psychiatry Res. The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study Mol Neurobiol.
