A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior
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ABSTRACT:
PROVIDER: PRJNA886964 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21799058.fastq.gz | Fastqsanger.gz | |||
| SRR21799059.fastq.gz | Fastqsanger.gz |
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Project description:The single nucleotide polymorphism rs13166360, causing a substitution of valine 147 to leucine in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that this missense mutation diminishes ADCY2 activity by altering its subcellular localization. Mice homozygous for the leucine variant display signs of a mania-like state accompanied by cognitive impairments. Mutant mice are hypersensitive to amphetamine and mania-like behaviors are responsive to lithium treatment. Exposure to chronic social defeat stress switches homozygous leucine variant carriers from a mania- to a depressive-like state. Single-cell RNA-seq revealed widespread expression of ADCY2 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 providing insights into underlying disease mechanisms potentially opening novel avenues for therapeutic intervention strategies.
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Project description:Mice with the two calcium-stmulated adenylyl cyclase isoforms (AC1 and AC8; DKO mice) knocked-out show conditioned fear memory deficits. We assessed gene expression changes at baseline and several time points after conditioned fear learning to assess transcriptional changes at different stages of learning. Transcriptional changes were assessed in the amydgdala and hippocampus of DKO and wild-type mice.
2010-10-19 | GSE23008 | GEO
Project description:The single nucleotide polymorphism rs13166360, causing a substitution of valine (Val) 147 to leucine (Leu) in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3',5'-cylic adenosine monophosphate (cAMP) by altering its subcellular localization. We established mice specifically carrying the Val to Leu substitution using CRISPR/Cas9-based gene editing. 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.e., they are hypersensitive to amphetamine, the observed mania-like behaviors are responsive to lithium treatment and the Val to Leu substitution results in a shifted excitatory/inhibitory synaptic balance towards more excitation. 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.
| S-EPMC11649569 | biostudies-literature
Project description:Transcriptional changes associated with chemical induction of adenylyl cyclase activity in Mtb
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Project description:Bipolar disorder (BD) is a psychiatric disorder in which the core feature is pathological disturbance in mood ranging from extreme elation (mania) to severe depression. Study has shown an aberrant pro-inflammatory status of monocytes/macrophages in mood disorders. Therefore, this study aimed at studying the monocyte compartment in Bipolar Disorder, by transcription profiling of CD14+ monocytes in patients and controls.
2008-01-01 | E-MEXP-1275 | biostudies-arrayexpress
Project description:Human infertility has become a medical and social health problem globally. Mice deficient in type 3 adenylyl cyclase (AC3), a key enzyme that synthesizes cyclic adenosine monophosphate (cAMP), develop male infertility but its underlying molecular mechanisms are still unknown. Here, we performed label-free quantitative (LFQ) proteomics study to identify testicular differentially expressed proteins (DEPs) and their respective biological processes.
2021-07-19 | PXD027382 |
Project description:Mice with the two calcium-stmulated adenylyl cyclase isoforms (AC1 and AC8; DKO mice) knocked-out show conditioned fear memory deficits. We assessed gene expression changes at baseline and several time points after conditioned fear learning to assess transcriptional changes at different stages of learning. Transcriptional changes were assessed in the amydgdala and hippocampus of DKO and wild-type mice. Mice either received no treatment (baseline) or were subjected to conditioned fear training (one 0.7mA x 2 sec shock). Amygdala and hippocampal tissue from wild-type and DKO (AC1 and AC8 KO) mice was used. Samples were extracted at baseline (-5 min before conditioned fear training), 0 hr, 1 hr, or 48 hr after a 5 min conditioned fear training trial, or at 1 wk after a 5 min conditioned fear testing trial. RNA samples from 5-10 mice were pooled per array with one array per genotype/brain region/time point for a total of 20 arrays. mRNA was reverese transcribed, labeled and hybridized to Affymetric Mouse Gene ST 1.0 Arrays.
2010-10-19 | E-GEOD-23008 | biostudies-arrayexpress
Project description:Goal: Assess transcriptional changes in Mtb associated with activation of adenylyl cyclase activity in the bacterium, by treatment with the Rv1625c agonist V-59 or activation of the TetOn-cAMP construct. Specifically, address changes in transcription of cholestrrol utilization genes, during growth of Mtb in cholesterol media. Method: WT, Rv1625c knockout, and Rv1625c Complement strains of Mtb were grown in cholesterol-based media and treated with V-59 or vehicle control (DMSO). V-59 is known to increase cAMP synthesis in WT, but not in Rv1625c knockout Mtb. V-59 increases cAMP synthesis above that observed in WT in the Complement strain, due to Rv1625c overexpression in this strain. Also, utilized TetOn-cAMP Mtb strain, to induce cAMP synthesis independent of V-59 and Rv1625c. Treatment with Atc induces expression of catalytic domain of Rv1264 in this strain. We grew the TetOn-cAMP strain in cholesterol-based media, treated with Atc or EtOH (vehicle control). Conclusions: Transcriptional changes to cholesterol utilization genes associated with V-59 treatment in WT Mtb were similar to those associated with TetOn-cAMP induction. The transcriptional changes associated with blockade of cholesterol degradation following V-59 treatment in WT Mtb were not observed in the Rv1625c knockout strain. The Rv1625c knockout strain had intrinsic defects in induction of cholesterol utilization genes. The Complement strain showed enhanced transcriptional changes in response to V-59 treatment.
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