Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a

Genetic analyses have linked microRNA-137 (MIR137) to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder. miR-137 plays important roles in neurogenesis and neuronal maturation, but the impact of miR-137 loss-of-function in vivo remains unclear. Here we show the complete loss of miR-137 in the mouse germline (gKO) or nervous system (cKO) leads to postnatal lethality, while heterozygous gKO and cKO mice remain viable. Partial loss of miR-137 in heterozygous cKO mice results in dysregulated synaptic plasticity, repetitive behavior, and impaired learning and social behavior. Transcriptomic and proteomic analyses revealed that the miR-137 mRNA target, phosphodiesterase 10a (Pde10a), is elevated in heterozygous knockout mice. Treatment with the Pde10a inhibitor papaverine or knockdown of Pde10a ameliorates the deficits observed in the heterozygous cKO mice. Collectively, our results suggest that MIR137 plays essential roles in postnatal neurodevelopment and that dysregulation of miR-137 potentially contributes to neuropsychiatric disorders in humans. Systematically investigate the role of miR-137 in neurodevelopment by using miR-137 knockout mice遗传分析已将微小RNA-137（microRNA-137，缩写为MIR137）与精神分裂症、孤独症谱系障碍等神经精神疾病建立了关联。miR-137在神经发生与神经元成熟过程中发挥重要作用，但体内miR-137功能丧失的影响仍未明确。本研究证实，在小鼠生殖系（germline knockout，简称gKO）或神经系统（conditional knockout，简称cKO）中完全缺失miR-137会导致出生后致死，而杂合子gKO与cKO小鼠均可存活。杂合子cKO小鼠中miR-137的部分缺失会引发突触可塑性失调、重复行为以及学习与社交行为受损。转录组学与蛋白质组学分析显示，miR-137的mRNA靶标磷酸二酯酶10A（phosphodiesterase 10a，简称Pde10a）在杂合子敲除小鼠中表达上调。采用Pde10a抑制剂罂粟碱（papaverine）进行干预，或敲低Pde10a的表达，可改善杂合子cKO小鼠出现的行为缺陷。综上，本研究结果表明MIR137在出生后神经发育过程中发挥关键作用，而miR-137的表达失调可能参与人类神经精神疾病的发生。本研究通过构建miR-137敲除小鼠，系统探究了miR-137在神经发育中的作用。