A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior

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. Single-cell RNA sequencing of ventral hippocampus of wild-type (ADCY2-V151) and mutant (ADCY2-L151) ADCY2 mice.腺苷酸环化酶2（ADCY2）中第147位缬氨酸替换为亮氨酸的单核苷酸多态性rs13166360，此前已被证实与双相情感障碍（BD）相关。本研究发现，该错义突变通过改变ADCY2的亚细胞定位，降低了其酶活性。携带亮氨酸纯合变异的小鼠表现出躁狂样状态，并伴随认知功能障碍；突变小鼠对苯丙胺具有高敏感性，且其躁狂样行为可通过锂盐治疗得到缓解。暴露于慢性社交挫败应激后，纯合亮氨酸变异携带者小鼠会从躁狂样状态转换为抑郁样状态。单细胞RNA测序（single-cell RNA-seq）结果显示，ADCY2在多种海马细胞类型中广泛表达。尤其在谷氨酸能CA1神经元中鉴定出的差异表达基因，提示ADCY2变异可通过包括cAMP相关信号通路在内的多个生物学过程引发功能改变。本研究验证了ADCY2作为BD风险基因的地位，为解析该疾病的潜在发病机制提供了新见解，同时有望为治疗干预策略开辟全新方向。本数据集包含野生型（ADCY2-V151）与突变型（ADCY2-L151）ADCY2小鼠腹侧海马的单细胞RNA测序数据。