Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility.
Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility.
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大脑特异性删除 GIT1 会损害认知并改变与精神分裂症易感性有关的突触蛋白网络的磷酸化。
DOI：
10.1038/s41380-022-01557-z
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发表时间：
2022-08
影响因子：
11
通讯作者：
Haggarty, Stephen J.
中科院分区：
文献类型：
--
作者：
Fass, Daniel M.;Lewis, Michael C.;Ahmad, Rushdy;Szucs, Matthew J.;Zhang, Qiangge;Fleishman, Morgan;Wang, Dongqing;Kim, Myung Jong;Biag, Jonathan;Carr, Steven A.;Scolnick, Edward M.;Premont, Richard T.;Haggarty, Stephen J.
Despite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and found that these mice have deficits in fear conditioning memory recall and spatial memory, as well as reduced cortical neuron dendritic spine density. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute specifically to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.
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影响因子：
3.7
作者：
Martyn AC;Toth K;Schmalzigaug R;Hedrick NG;Rodriguiz RM;Yasuda R;Wetsel WC;Premont RT
通讯作者：
Premont RT
影响因子：
10.6
作者：
Datta D;Arion D;Corradi JP;Lewis DA
通讯作者：
Lewis DA
影响因子：
5.5
作者：
Aslan, Joseph E.;Baker, Sandra M.;McCarty, Owen J. T.
通讯作者：
McCarty, Owen J. T.
影响因子：
16.2
作者：
Boyken, Janina;Gronborg, Mads;Chua, John Jia En
通讯作者：
Chua, John Jia En
影响因子：
4.8
作者：
Fu, CA;Shen, M;Luo, Y
通讯作者：
Luo, Y