Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities.

Kenichiro Nagahama, Kazuto Sakoori, Takaki Watanabe, Yusuke Kishi, Keita Kawaji, Michinori Koebis, Kazuki Nakao, Yukiko Gotoh, Atsu Aiba, Naofumi Uesaka, Masanobu Kano

Cell reports 2020 Sep 15

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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. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Kenichiro Nagahama, Kazuto Sakoori, Takaki Watanabe, Yusuke Kishi, Keita Kawaji, Michinori Koebis, Kazuki Nakao, Yukiko Gotoh, Atsu Aiba, Naofumi Uesaka, Masanobu Kano. Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities. Cell reports. 2020 Sep 15;32(11):108126