Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Li, Jun; Chai, Anping; Wang, Lifang; Ma, Yuanlin; Wu, Zhiliu; Yu, Hao; Mei, Liwei; Lü, Lin; Zhang, Chen; Yue, Weihua; Xu, Lin; Rao, Yi; Zhang, Dai

doi:10.1073/pnas.1512913112

Cited by 58 publications

(78 citation statements)

References 48 publications

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“…The cytoplasmic FMRP-interacting protein (CYFIP) directly links Rac1 and FMRP to modulate cytoskeleton remodeling (45); Tsc1 functionally regulates Rac1 activity (46,60); Ube3a promotes Rho-GEF Pbl degradation via ubiquitination to affect Rac1 activation (47); and upon synaptic activation Rho-GEF Kal-7 disassembles from the Nrx-1/Nlg4/DISC1 complex to modulate the Rac1 pathway (48). Several other autism-risk genes, such as Nlg1, Nrx-4, P-Rex1, and Shank-3, have also been reported to participate in the Rac1-signaling pathway (61)(62)(63)(64). In addition, when the gene-environment interactions of 122 genes and 191 factors in the autistic context were analyzed by systems biology, Rac1 was predicted to be a converging node that genetically links to the neurobiology of autism (27,65)…”

Section: Discussionmentioning

confidence: 99%

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

Dong

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of autism is so complicated because it involves the effects of variants of several hundred risk genes along with the contribution of environmental factors. Therefore, it has been challenging to identify the causal paths that lead to the core autistic symptoms such as social deficit, repetitive behaviors, and behavioral inflexibility. As an alternative approach, extensive efforts have been devoted to identifying the convergence of the targets and functions of the autism-risk genes to facilitate mapping out causal paths. In this study, we used a reversal-learning task to measure behavioral flexibility in Drosophila and determined the effects of loss-of-function mutations in multiple autism-risk gene homologs in flies. Mutations of five autism-risk genes with diversified molecular functions all led to a similar phenotype of behavioral inflexibility indicated by impaired reversal-learning. These reversal-learning defects resulted from the inability to forget or rather, specifically, to activate Rac1 (Ras-related C3 botulinum toxin substrate 1)-dependent forgetting. Thus, behavior-evoked activation of Rac1-dependent forgetting has a converging function for autism-risk genes.A utism spectrum disorders are common polygenic neurodevelopmental disorders diagnosed by a cluster of core clinical syndromes characterized by impaired social interaction, communication deficits, and behavioral inflexibility (1-3). A large number of autism-risk genes have been identified through different genetic approaches (4-8). These candidate genes play highly diversified roles in synaptic organization, transmission, intracellular signaling pathways, and protein expression regulation, among others (9). How do variants of these risk genes lead to the core symptoms of autism? Are there causal paths that can determine the onset of autism? Answering these questions is difficult because the disorder is multifactorial in nature with multiple genetic variants and environmental factors contributing to the core symptoms (10-13). To face this challenge, extensive efforts have been made to identify the targeting and functional convergence of the autism-risk genes, such as those involved in translation regulation (14-16) and long-range connectivity among different brain regions (17)(18)(19). These targets and functions provide a better biological basis for elucidating the causal paths between risk genes and the disorders of autism.The aim of the this study was to determine whether Rac1 (Rasrelated C3 botulinum toxin substrate 1)-dependent forgetting is a functional converging point for autism-risk genes. This idea was inspired by two clues. First, inhibition of Rac1 activity in Drosophila leads to the failure to activate Rac1-dependent forgetting, resulting in behavioral inflexibility as assayed through a reversal-learning task (20). Behavioral inflexibility has been observed frequently in the clinical studies of autism patients (21,22), and children with autism are reported to have impaired reversal-learning, although they can learn new beh...

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Section: Discussionmentioning

confidence: 99%

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

Dong

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…One systems biology study based on gene-expression analysis of cerebellar samples concluded that Rac1 plays a critical role in the neuropathological events associated with ASD (Zeidán-Chuliá F, et al, 2013). Another recent study found that autism is associated with genetic variation and copy number deletion of P-Rex1, which encodes phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 (Li et al, 2015). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the mouse hippocampus produces ASD-like behaviors, including impaired social interactions, reversal learning deficits in the water maze, and extinction-resistant memory of fear conditioning.…”

Section: Active Forgetting Autism Spectrum Disorders and Other Brainmentioning

confidence: 99%

The Biology of Forgetting—A Perspective

Davis

Zhong

2017

Neuron

246

268

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Pioneering research studies, beginning with those using Drosophila, have identified several molecular and cellular mechanisms for active forgetting. The currently known mechanisms for active forgetting include neurogenesis-based forgetting, interference-based forgetting, and intrinsic forgetting, the latter term describing the brain’s chronic signaling systems that function to slowly degrade molecular and cellular memory traces. The best-characterized pathway for intrinsic forgetting includes “forgetting cells” that release dopamine onto engram cells, mobilizing a signaling pathway that terminates in the activation of Rac1/cofilin to effect changes in the actin cytoskeleton and neuron/synapse structure. Intrinsic forgetting may be the default state of the brain, constantly promoting memory erasure and competing with processes that promote memory stability like consolidation. A better understanding of active forgetting will provide insights into the brain’s memory management system and human brain disorders that alter active forgetting mechanisms.

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“…Prex1 results in autismlike behavior 36 and is associated with antidepressant response in humans 37 . Interestingly, very few associations that were detected in deconvoluted neurons (1 CpG) or glia (14 CpGs) were also detected in bulk, suggesting celltypespecific effects are indeed diluted or obscured in bulk tissue.…”

Section: Bulk Brainmentioning

confidence: 99%

Cell-type-specific methylome-wide association studies implicate neurodegenerative processes and neuroimmune communication in major depressive disorder

Chan

Turecki

Shabalin

et al. 2018

Preprint

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We studied the methylome in three collections of human postmortem brain (N=206) and blood samples (N=1,132) of subjects with major depressive disorder (MDD) and controls. Using an epigenomic deconvolution approach we performed celltypespecific methylomewide association studies (MWAS) within subpopulations of neurons/glia and granulocytes/Tcells/Bcells/monocytes for bulk brain and blood data, respectively. Multiple MWAS findings in neurons/glia replicated across brain collections (ORs=509538, Pvalues<1x10 5 ) and were reproducible in an arraybased MWAS of sorted neurons/glia from a fourth brain collection (N=58). Pathway analyses implicated p75 NTR /VEGF signaling, neurodegeneration, and bloodbrain barrier perturbation. Celltype specific analysis in blood identified associations in CD14+ monocytes a cell type strongly linked to neuroimmune processes and stress. Top results in neurons/glia/bulk and monocytes were enriched for genes supported by GWAS for MDD (ORs=2.022.87, Pvalues=0.003 to <1x10 5 ), neurodegeneration and other psychiatric disorders. In summary, we identified novel MDDmethylation associations by using epigenomic deconvolution that provided important mechanistic insights for the disease.

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Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Cited by 58 publications

References 48 publications

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

The Biology of Forgetting—A Perspective

Cell-type-specific methylome-wide association studies implicate neurodegenerative processes and neuroimmune communication in major depressive disorder

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