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 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 [ 2526 dating someone with manic depression, 27282930 ] 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 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 dating someone with manic depression 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.
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Therapy spectrum
It is argued that among studies that were published within recent decades to this. This relationship, however. Bipolar affective disorder is a serious mood disorder characterized by manic and depressive mood swings. Compares development within the fields of medical genetics and psychiatry. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which. Objective: Research in adults has identified an association between bipolar disorder and suicidal behavior.Regional Center of Radiation Protection RSZ WHO REMPAN Collaborating Center. Recording, tracking and scoring of animal behaviors was carried out using the automated video tracking system ANY-maze ANY-maze 6. However, while the performance of the stressed WT mice was indistinguishable from WT control mice, L mice displayed a significant reduction in the time spent in the inner zone Fig. Gordovez FJA, McMahon FJ. J Clin Psychiatry. Article PubMed PubMed Central CAS Google Scholar Sidor MM, Spencer SM, Dzirasa K, Parekh PK, Tye KM, Warden MR, et al. Mol Psychiatry 30 , 97— The project was supported by the Max Planck Society JMD and the German Ministry of Science and Education IntegraMent: Integrated Understanding of Causes and Mechanisms in Mental Disorders FKZ 01ZXH, WW; FKZ 01KU, JMD. Hines LM, Hoffman PL, Bhave S, Saba L, Kaiser A, Snell L, et al. Download references. J Neural Transm Vienna. German Center for Neurodegenerative Diseases DZNE site Munich, , Munich, Germany. Similarly, assessment of cAMP production kinetics confirmed a reduced baseline activity of the ADCY2-L variant Fig. In addition, our own psychoeducation groups provide basic knowledge about the disorder and how to deal with the affected family member. 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. Substitution of valine for leucine in factor VIIa increases the intrinsic enzymatic activity. Therefore, we investigated the expression of the synaptic vesicle protein synapsin 1 SYN1 as a presynaptic marker. Thank you for your interest in our newsletter. Art and Science. Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2 Article 24 November People with bipolar disorder may experience alternating phases of elation and depression. Homozygous mutant L mice show signs of a mania-like state Next, we aimed at investigating the in vivo consequences of rs on mouse behavior. Nevertheless, L mice presented with significantly reduced anxiety-related behavior in these tests. J Bone Miner Metab. Article PubMed CAS Google Scholar Gros R, Ding Q, Cao H, Main T, Hegele RA, Feldman RD. Here we demonstrate that rs directly interferes with ADCY2 activity, diminishing its capacity to generate cAMP. Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP.
