SETD1A encodes a histone methyltransferase whose de novo mutations are identified in schizophrenia (SCZ) patients and confer a large increase in disease risk. Here, we generate Setd1a mutant mice carrying the frameshift mutation that closely mimics a loss-of-function variant of SCZ. Our Setd1a (+/−) mice display various behavioral abnormalities relevant to features of SCZ, impaired excitatory synaptic transmission in layer 2/3 (L2/3) pyramidal neurons of the medial prefrontal cortex (mPFC), and altered expression of diverse genes related to neurodevelopmental disorders and synaptic functions in the mPFC. RNAi-mediated Setd1a knockdown (KD) specifically in L2/3 pyramidal neurons of the mPFC only recapitulates impaired sociality among multiple behavioral abnormalities of Setd1a (+/−) mice. Optogenetics-assisted selective stimulation of presynaptic neurons combined with Setd1a KD reveals that Setd1a at postsynaptic site is essential for excitatory synaptic transmission. Our findings suggest that reduced SETD1A may attenuate excitatory synaptic function and contribute to the pathophysiology of SCZ.

SETD1A编码一种组蛋白甲基转移酶，其在精神分裂症（SCZ）患者中发现了从头突变，并大大增加了疾病风险。在这里，我们生成了Setd1a突变小鼠，它们携带的移码突变非常类似于SCZ的功能丧失变体。我们的Setd1a（+/-）小鼠表现出与SCZ特征相关的各种行为异常，内侧前额叶皮层（mPFC）的第2/3（L2 / 3）层锥体神经元兴奋性突触传递受损以及与相关基因相关的表达变化对mPFC中的神经发育障碍和突触功能的影响。RNAi介导的Setd1a敲除（KD）专门在mPFC的L2 / 3锥体神经元中只能概括Setd1a（+/-）小鼠多种行为异常中的社交能力受损。光遗传学辅助的与Setd1a KD结合的突触前神经元的选择性刺激显示，在突触后位点的Setd1a对于兴奋性突触传递至关重要。我们的发现表明，减少的SETD1A可能减弱兴奋性突触功能，并有助于SCZ的病理生理。