Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
Pfizer, Andover, MA, USA.
Mol Psychiatry. 2017 Dec;22(12):1714-1724. doi: 10.1038/mp.2016.155. Epub 2016 Sep 20.
Lithium responsivity in patients with bipolar disorder has been genetically associated with Phosphodiesterase 11A (PDE11A), and lithium decreases PDE11A mRNA in induced pluripotent stem cell-derived hippocampal neurons originating from lithium-responsive patients. PDE11 is an enzyme uniquely enriched in the hippocampus that breaks down cyclic AMP and cyclic GMP. Here we determined whether decreasing PDE11A expression is sufficient to increase lithium responsivity in mice. In dorsal hippocampus and ventral hippocampus (VHIPP), lithium-responsive C57BL/6J and 129S6/SvEvTac mice show decreased PDE11A4 protein expression relative to lithium-unresponsive BALB/cJ mice. In VHIPP, C57BL/6J mice also show differences in PDE11A4 compartmentalization relative to BALB/cJ mice. In contrast, neither PDE2A nor PDE10A expression differ among the strains. The compartment-specific differences in PDE11A4 protein expression are explained by a coding single-nucleotide polymorphism (SNP) at amino acid 499, which falls within the GAF-B homodimerization domain. Relative to the BALB/cJ 499T, the C57BL/6J 499A decreases PDE11A4 homodimerization, which removes PDE11A4 from the membrane. Consistent with the observation that lower PDE11A4 expression correlates with better lithium responsiveness, we found that Pde11a knockout mice (KO) given 0.4% lithium chow for 3+ weeks exhibit greater lithium responsivity relative to wild-type (WT) littermates in tail suspension, an antidepressant-predictive assay, and amphetamine hyperlocomotion, an anti-manic predictive assay. Reduced PDE11A4 expression may represent a lithium-sensitive pathophysiology, because both C57BL/6J and Pde11a KO mice show increased expression of the pro-inflammatory cytokine interleukin-6 (IL-6) relative to BALB/cJ and PDE11A WT mice, respectively. Our finding that PDE11A4 negatively regulates lithium responsivity in mice suggests that the PDE11A SNPs identified in patients may be functionally relevant.
双相情感障碍患者的锂反应性已在基因上与磷酸二酯酶 11A（PDE11A）相关联，并且锂可降低源自锂反应性患者的诱导多能干细胞衍生的海马神经元中的 PDE11A mRNA。PDE11 是一种在海马体中独特丰富的酶，可分解环 AMP 和环 GMP。在这里，我们确定降低 PDE11A 表达是否足以增加小鼠对锂的反应性。在背侧海马体和腹侧海马体（VHIPP）中，与锂不敏感的 BALB/cJ 小鼠相比，锂反应性 C57BL/6J 和 129S6/SvEvTac 小鼠显示 PDE11A4 蛋白表达降低。在 VHIPP 中，C57BL/6J 小鼠相对于 BALB/cJ 小鼠也显示 PDE11A4 区室化的差异。相比之下，这些品系之间的 PDE2A 或 PDE10A 表达均无差异。PDE11A4 蛋白表达的区室特异性差异可归因于位于 GAF-B 同源二聚化结构域内的氨基酸 499 处的编码单核苷酸多态性（SNP）。与 BALB/cJ 499T 相比，C57BL/6J 499A 降低了 PDE11A4 同源二聚化，从而将 PDE11A4 从膜上除去。与观察到的较低的 PDE11A4 表达与更好的锂反应性相关的结果一致，我们发现，给予 0.4％锂饮食 3 周以上的 Pde11a 敲除（KO）小鼠在尾悬试验（一种抗抑郁预测试验）和安非他命过度运动（一种抗躁狂预测试验）中相对于野生型（WT）同窝仔鼠表现出更高的锂反应性。降低的 PDE11A4 表达可能代表一种对锂敏感的病理生理学，因为与 BALB/cJ 和 PDE11A WT 小鼠相比，C57BL/6J 和 Pde11a KO 小鼠的促炎细胞因子白细胞介素-6（IL-6）表达均增加。我们发现 PDE11A4 负调节小鼠对锂的反应性，表明在患者中鉴定出的 PDE11A SNPs 可能具有功能相关性。
