Thank you for visiting nature. You are using bipolar disorder and dating 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 bipolar disorder and dating 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 bipolar disorder and dating 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 bipolar disorder and dating 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. Bipolar disorder and dating 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.
Internationale Patentnummer. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Thus, it is not surprising that the observed alteration in ADCY2 activity due to the ValLeu substitution resulted in differential gene expression, particularly in CA1 glutamatergic neurons but also in oligodendrocytes and, to a lesser extent, in astrocytes. While previous research suggests associations between BD and traits from the NEO-FFI profiles, the current study firstly aimed to identify latent classes of NEO-FFI profiles, and, secondly, to examine their impact on the longterm prognosis of BD. Article PubMed PubMed Central CAS Google Scholar Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B, et al. Moreover, L mice transitioned from an active to a passive stress-coping strategy in the FST.
Introduction
Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3',5'-cylic. PDF | Deficits of theory of mind and empathy have been reported in bipolar disorder and schizophrenia Daten, MASC-Para-. meter und IRI-Ska-. 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).Article PubMed CAS Google Scholar Sadana R, Dessauer CW. Accordingly, mouse models of BD particularly show reversibility of manic-like symptoms in response to lithium treatment [ 35 , 39 ]. Einige Funktionen dieser Seite funktionieren ohne JavaScript nicht. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4. Article PubMed Google Scholar Griebel G, Holsboer F. While anxiety-related and stress-coping behavior were largely unaffected in WT mice, L mice profoundly responded to the CSDS paradigm. Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model. Brain imaging biomarkers : Brain imaging, such as MRI and PET scans, can be used to measure brain structure and activity in people with bipolar disorder. Address Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie des Universitätsklinikums Margarete-Höppel-Platz 1 Würzburg Deutschland. The altered frequency of mEPSCs and mIPSCs suggest alterations in synaptic release probabilities. All experiments were conducted with adult male mice age: 2—5 months. Nevertheless, the scRNA-Seq approach serves here as an initial screen which requires independent confirmation of DEGs and related pathways. Download references. Article PubMed CAS Google Scholar Seifert R, Lushington GH, Mou TC, Gille A, Sprang SR. Autor:innen Carls-Diamante, Sidney. Dateien Zu diesem Dokument gibt es keine Dateien. Concomitantly, we found higher DA levels in response to amphetamine in L mice in regions innervated by midbrain dopaminergic neurons. The mechanisms of action of lithium. Genome-wide association study identifies 30 loci associated with bipolar disorder. In: Philosophical Explorations. Selective amplification and sequencing of predicted off-target sites co-localized with Adcy2 on chromosome 13, which might escape segregation during meiosis, did not reveal any undesired off-target effects. Advanced search. Maternal stress, prenatal medical illnesses and obstetric complications: Risk factors for schizophrenia spectrum disorder, bipolar disorder and major depressive disorder. Amphetamine treatment generally resulted in increased DA levels compared to saline treatment. Institute of Developmental Genetics, Helmholtz Zentrum München, , Neuherberg, Germany. PLoS One. Zhuang X, Oosting RS, Jones SR, Gainetdinov RR, Miller GW, Caron MG, et al. Article PubMed PubMed Central CAS Google Scholar Muhleisen TW, Leber M, Schulze TG, Strohmaier J, Degenhardt F, Treutlein J, et al. Its causes are manifold and for the most part still not understood. Ethics declarations Competing interests The authors declare no competing interests. Article PubMed CAS Google Scholar Wong ST, Athos J, Figueroa XA, Pineda VV, Schaefer ML, Chavkin CC, et al. Wray NR, Pergadia ML, Blackwood DH, Penninx BW, Gordon SD, Nyholt DR, et al. Article PubMed PubMed Central Google Scholar.
