Neurexin‐1 is required for synapse formation and larvae associative learning in <i>Drosophila</i>

Zeng, Xiankun; Sun, Mingkuan; Liu, Li; Chen, Fading; Wei, Liuchan; Xie, Wei

doi:10.1016/j.febslet.2007.04.068

Cited by 94 publications

(150 citation statements)

References 21 publications

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“…The stronger functional association of the neurexin-neuroligin complex with GABA compared with glutamate synapses in coculture and in the knock-out mice may reflect a greater redundancy of synaptic organizing molecules at glutamate synapses. In Drosophila, which lack ␤ neurexins and have less redundancy in general, null mutations in the single ␣ neurexin gene lead to a reduction in numbers of central and neuromuscular synapses, altered ultrastructure, and defects in synaptic transmission and associative learning (59,60).…”

Section: Discussionmentioning

confidence: 99%

Induction of GABAergic Postsynaptic Differentiation by α-Neurexins

Kang

Zhang

Dobie

et al. 2008

Journal of Biological Chemistry

117

109

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␤-Neurexin and neuroligin cell adhesion molecules contribute to synapse development in the brain. The longer ␣-neurexins function at both glutamate and ␥-aminobutyric acid (GABA) synapses in coupling to presynaptic calcium channels. Binding of ␣-neurexins to neuroligins was recently reported, but the role of the ␣-neurexins in synapse development has not been well studied. Here we report that in COS cell neuron coculture assays, all three ␣-neurexins induce clustering of the GABAergic postsynaptic scaffolding protein gephyrin and neuroligin 2 but not of the glutamatergic postsynaptic scaffolding protein PSD-95 or neuroligin 1/3/4. ␣-Neurexins also induce clustering of the GABA A receptor ␥2 subunit. This synapse promoting activity of ␣-neurexins is mediated by the sixth LNS (laminin neurexin sex hormone-binding protein) domain and negatively modulated by upstream sequences. Although inserts at splice site 4 (S4) in ␤-neurexins promote greater clustering activity for GABA than glutamate proteins in coculture assay, ␣-neurexinspecific sequences confer complete specificity for GABA proteins. We further report a developmental increase in the ratio of ؊S4 to ؉S4 forms of neurexins correlating with an increase in glutamate relative to GABA synaptogenesis and activity regulation of splicing at S4. Thus, ؉S4 ␤-neurexins and, even more selectively, ␣-neurexins may be mediators of GABAergic synaptic protein recruitment and stabilization.

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Section: Discussionmentioning

confidence: 99%

Induction of GABAergic Postsynaptic Differentiation by α-Neurexins

Kang

Zhang

Dobie

et al. 2008

Journal of Biological Chemistry

117

109

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“…In addition to behavioral flexibility, the autism genes in our study participate in some other cognitive processes such as learning and long-term memory (29,33,69,70). For instance, as a general translational repressor, Fmr1 interacts with Staufen and the RNAi pathway to regulate long-term memory formation.…”

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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“…As we know Drosophila has only one neurexin gene, dnrx (27,28), we wanted to know whether DNrx expression and localization are altered in dnlg3 mutants. First, we examined expression and localization of DNrx in both WT and dnlg3 mutants central nerve system.…”

Section: Normal Expression and Localization Of Dnrx In Dnlg3mentioning

confidence: 99%

Drosophila Neuroligin3 Regulates Neuromuscular Junction Development and Synaptic Differentiation

Xing

Gan

Chen

et al. 2014

Journal of Biological Chemistry

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Background: Postsynaptic neuroligins play essential roles in synaptic maturation and function. Results: Drosophila Neuroligin3 regulates neuromuscular junction growth, GluRIIA recruitment, synaptic vesicle recycling, and postsynaptic density maturation. Conclusion: This elucidates the in vivo roles of Drosophila Neuroligin3 in development and synaptic differentiation of NMJs. Significance: This highlights that Drosophila can be used to understand and uncover functional diversity in neuroligins.

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Neurexin‐1 is required for synapse formation and larvae associative learning in Drosophila

Cited by 94 publications

References 21 publications

Induction of GABAergic Postsynaptic Differentiation by α-Neurexins

Induction of GABAergic Postsynaptic Differentiation by α-Neurexins

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

Drosophila Neuroligin3 Regulates Neuromuscular Junction Development and Synaptic Differentiation

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