Neurexins and neuropsychiatric disorders

Kasem, Enas; Kurihara, Taiga; Tabuchi, Katsuhiko

doi:10.1016/j.neures.2017.10.012

Cited by 99 publications

(100 citation statements)

References 86 publications

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“…Whether the expression of Nrxn1 in astrocytes is physiologically significant and whether astrocytes contribute to synaptic transmission via a Nrxn1-dependent pathway has not been examined. Importantly, copy number variations (CNVs) that selectively alter expression of Nrxn1 (encoded by the NRXN1 gene in humans) are among the most frequent single-gene mutations observed in patients with schizophrenia, Tourette syndrome, autism, and other neurodevelopmental disorders (reviewed in Kasem et al, 2018;Südhof, 2017), suggesting that heterozygous loss-of-function of NRXN1 predisposes to neuropsychiatric diseases.…”

Section: Introductionmentioning

confidence: 99%

Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

Trotter

Dargaei

Sclip

et al. 2020

Preprint

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At tripartite synapses, astrocytes surround synaptic contacts, but how astrocytes contribute to the assembly and function of synapses remains unclear. Here we show that neurexin-1α, a presynaptic adhesion molecule that controls synapse properties, is also abundantly expressed by astrocytes. Strikingly, astrocytic neurexin-1α, but not neuronal neurexin-1α, is highly modified by heparan sulfate. Moreover, astrocytic neurexin-1α is uniquely alternatively spliced and invariably contains an insert in splice-site #4, thereby restricting the range of ligands to which it binds. Deletion of neurexin-1 from astrocytes or neurons does not alter synapse numbers or synapse ultrastructure, but differentially impairs synapse function. At hippocampal Schaffer-collateral synapses, neuronal neurexin-1 is essential for normal NMDA-receptor-mediated synaptic responses, whereas astrocytic neurexin-1 is required for normal AMPA-receptor-mediated synaptic responses and for long-term potentiation of these responses. Thus, astrocytes directly shape synapse properties via a neurexin-1-dependent mechanism that involves a specific molecular program distinct from that of neuronal neurexin-1.

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Section: Introductionmentioning

confidence: 99%

Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

Trotter

Dargaei

Sclip

et al. 2020

Preprint

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“…NRXs and LAR-RPTPs act as presynaptic molecular hubs to trans-synaptically regulate synapse structure and function by making multiple trans-interactions with their specific postsynaptic organizers, such as NRX-neuroligin (NLGN), NRX-leucine-rich-repeat transmembrane neuronal proteins (LRRTMs), PTPσ-neurotrophin receptor tropomyosin-related kinase C (TrkC), PTPσ/δ-Slit and Trk-like proteins (Slitrks), LAR-netrin-G-ligand 3 (NGL3) and so on (Takahashi and Craig, 2013 ; Südhof, 2017 ; Figure 1 ). The most well-studied synaptic organizing complex is the NRX-NLGN complex, essential for synapse organization, transmission and plasticity as well as genetically linked with cognitive disorders such as autism spectrum disorders (ASD) and schizophrenia (Craig and Kang, 2007 ; Südhof, 2008 , 2017 ; Kasem et al, 2018 ). Given the evidence of synaptic impairments in AD, recent studies have been trying to test whether and how Aβ interferes with synaptic organizers because of their pivotal roles in synapse physiology and cognitive function.…”

Section: Introductionmentioning

confidence: 99%

Synaptic Organizers in Alzheimer’s Disease: A Classification Based on Amyloid-β Sensitivity

Lee

Khaled

Chofflet

et al. 2020

Front. Cell. Neurosci.

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Synaptic pathology is one of the major hallmarks observed from the early stage of Alzheimer’s disease (AD), leading to cognitive and memory impairment characteristic of AD patients. Synaptic connectivity and specificity are regulated by multiple trans-bindings between pre- and post-synaptic organizers, the complex of which exerts synaptogenic activity. Neurexins (NRXs) and Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are the major presynaptic organizers promoting synaptogenesis through their distinct binding to a wide array of postsynaptic organizers. Recent studies have shown that amyloid-β oligomers (AβOs), a major detrimental molecule in AD, interact with NRXs and neuroligin-1, an NRX-binding postsynaptic organizer, to cause synaptic impairment. On the other hand, LAR-RPTPs and their postsynaptic binding partners have no interaction with AβOs, and their synaptogenic activity is maintained even in the presence of AβOs. Here, we review the current evidence regarding the involvement of synaptic organizers in AD, with a focus on Aβ synaptic pathology, to propose a new classification where NRX-based and LAR-RPTP-based synaptic organizing complexes are classified into Aβ-sensitive and Aβ-insensitive synaptic organizers, respectively. We further discuss how their different Aβ sensitivity is involved in Aβ vulnerability and tolerance of synapses for exploring potential therapeutic approaches for AD.

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“…In the context of neurodevelopmental disorders, it is important to note that many are known to be caused by, or highly associated with, genetic mutations (Kasem et al, 2018;Leung and Jia, 2016;Penagarikano et al, 2007;Ramaswami and Geschwind, 2018;San Martin and Pagani, 2014). Genetic variations can severely impact brain maturation (e.g., dendritic morphologies and spine densities, cell number) and related developmental processes (including cognition) that ultimately result in the appearance of psychiatric-related behavioral dysfunction.…”

Section: The Importance Of Assessing Developmental Trajectoriesmentioning

confidence: 99%

Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders

Morè

Lauterborn

Papaleo

et al. 2020

Neuroscience & Biobehavioral Reviews

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Neurexins and neuropsychiatric disorders

Cited by 99 publications

References 86 publications

Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

Synaptic Organizers in Alzheimer’s Disease: A Classification Based on Amyloid-β Sensitivity

Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders

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