Setd1aInsufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities

SETD1Aencodes a histone methyltransferase whose de novomutations are identified in schizophrenia (SCZ) patients and confer a large increase in disease risk. Here, we generate Setd1amutant 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 Setd1aknockdown (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 Setd1aKD reveals that Setd1aat 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.