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 dating someone with manic depression 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 dating someone with manic depression 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 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 dating someone with manic depression 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 goal of treatment is to prevent relapse and recurrence, as the recurrent nature of the disorder can be destabilizing for those affected. Mol Neurobiol. Dienes KA, Hammen C, Henry RM, Cohen AN, Daley SE. Neurotransmitter levels : Levels of certain neurotransmitters, such as dopamine and serotonin, may be different in people with bipolar disorder. Montezinho LP, Mork A, Duarte CB, Penschuck S, Geraldes CF, Castro MM.
Causes and diagnosis
Objective: Research in adults has identified an association between bipolar disorder and suicidal behavior. 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. 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.Genome-wide association study identifies 30 loci associated with bipolar disorder. SHANK3 overexpressing mice showed a reduction in mIPSC frequency and an increased amplitude of spontaneous EPSCs sEPSCs which was accompanied by a reduction of inhibitory and an increase in excitatory synaptic markers [ 77 ] [ 76 ]. 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. Protein expression was assessed by Western blot and immunofluorescence. Tibbs ZE, Guidry AL, Falany JL, Kadlubar SA, Falany CN. To evaluate the impact of the ADCY2 missense mutation onto the transcriptional state of vHPC cell types, we performed differential gene expression analysis between WT and L conditions. Lopez JP, Lucken MD, Brivio E, Karamihalev S, Kos A, De Donno C, et al. Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. What are the ethics of representing mental illness? Razzoli M, Andreoli M, Maraia G, Di Francesco C, Arban R. Adcy2 VL mice were tested in a battery of behavioral paradigms to assess locomotion, exploratory and anxiety-related behavior, stress-coping strategies and cognitive performance. Taken together, these findings suggest a redistribution of the ADCY2-L variant from the plasma membrane to intracellular compartments. Statistical analyses were performed using the commercially available software GraphPad Prism v5. This serves as a criterion to distinguishing them from natural mood swings. All three ADCY2 variants showed comparable levels of protein expression in transiently transfected HEK cells Fig. In sum, the gene enrichment analysis revealed a wide range of processes and pathways which are potentially contributing to the behavioral alterations observed in L mice Fig. Pugliese V, Bruni A, Carbone EA, Calabro G, Cerminara G, Sampogna G, et al. Weitere Punkte. The functional redundancy, overlapping and low expression, lack of isoform specific agonist and antagonist as well as the absence of reliable antibodies are intricacies inherent to the research on ADCY family members in vivo [ 17 , 53 , 54 , 55 , 56 ]. We generated N-terminally HA- or FLAG-tagged wild-type ADCY2-V and mutant ADCY2-L variants of murine ADCY2, reflecting the human ValLeu substitution. L and WT mice showed similar physiological signs indicative of a chronically stressed state. Article PubMed CAS Google Scholar Zhuang X, Oosting RS, Jones SR, Gainetdinov RR, Miller GW, Caron MG, et al. Exp Mol Med. 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. Article PubMed Google Scholar Uher R. Dwivedi Y, Pandey GN. Mutations in these genes may increase the risk of developing the disorder. Article PubMed PubMed Central CAS Google Scholar Ostrom RS, Bogard AS, Gros R, Feldman RD. The family of mammalian membrane-bound ADCYs comprises 9 isoforms, which are classified according to their signaling properties. Lopez JP, Brivio E, Santambrogio A, De Donno C, Kos A, Peters M, et al. Neuroanatomical distribution and neurochemical characterization of cells expressing adenylyl cyclase isoforms in mouse and rat brain. Here we demonstrate that rs directly interferes with ADCY2 activity, diminishing its capacity to generate cAMP. Highlighted are the Alu I restriction site and the ValLeu substitution present in L mice.
