Department of Psychiatry and the Behavioral Sciences, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, USA.
Department of Psychiatry, University of California, San Diego, USA.
Sci Rep. 2018 Feb 2;8(1):2281. doi: 10.1038/s41598-018-20610-y.
The scaffold protein DLGAP1 is localized at the post-synaptic density (PSD) of glutamatergic neurons and is a component of supramolecular protein complexes organized by PSD95. Gain-of-function variants of DLGAP1 have been associated with obsessive-compulsive disorder (OCD), while haploinsufficient variants have been linked to autism spectrum disorder (ASD) and schizophrenia in human genetic studies. We tested male and female Dlgap1 wild type (WT), heterozygous (HT), and knockout (KO) mice in a battery of behavioral tests: open field, dig, splash, prepulse inhibition, forced swim, nest building, social approach, and sucrose preference. We also used biochemical approaches to examine the role of DLGAP1 in the organization of PSD protein complexes. Dlgap1 KO mice were most notable for disruption of protein interactions in the PSD, and deficits in sociability. Other behavioral measures were largely unaffected. Our data suggest that Dlgap1 knockout leads to PSD disruption and reduced sociability, consistent with reports of DLGAP1 haploinsufficient variants in schizophrenia and ASD.
支架蛋白 DLGAP1 定位于谷氨酸能神经元的突触后密度（PSD），是由 PSD95 组织的超分子蛋白复合物的组成部分。功能获得性 DLGAP1 变异与强迫症（OCD）有关，而单倍不足的变异与人类遗传研究中的自闭症谱系障碍（ASD）和精神分裂症有关。我们在一系列行为测试中测试了雄性和雌性 Dlgap1 野生型（WT）、杂合型（HT）和敲除型（KO）小鼠：旷场、挖掘、飞溅、前脉冲抑制、强迫游泳、筑巢、社交接近和蔗糖偏好。我们还使用生化方法来研究 DLGAP1 在 PSD 蛋白复合物组织中的作用。Dlgap1 KO 小鼠最显著的特征是 PSD 中蛋白质相互作用的破坏，以及社交能力的缺陷。其他行为测量基本不受影响。我们的数据表明，Dlgap1 敲除导致 PSD 破坏和社交能力降低，这与精神分裂症和 ASD 中 DLGAP1 单倍不足变异的报告一致。
