Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-related behavioral abnormalities

SETD1A encodes a histone methyltransferase whose de novo mutations are first identified in schizophrenia (SCZ) patients and confer a large increase in disease risk. We generated Setd1a mutant mice carrying the frameshift mutation that closely mimics a loss-of-function variant of SCZ. Our Setd1a het 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 specifically in L2/3 pyramidal neurons of the mPFC only recapitulates the impaired sociality among multiple behavioral abnormalities of Setd1a het mice. Optogenetics-assisted selective stimulation of presynaptic neurons combined with Setd1a-knockdown 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 pathophysiology of SCZ.