A Modular Organization of LRR Protein-Mediated Synaptic Adhesion Defines Synapse Identity

Schroeder, Anna; Vanderlinden, Julie; Vints, Katlijn; Ribeiro, Luís F.; Vennekens, Kristel M.; Gounko, Natalia V.; Wierda, Keimpe; Wit, Joris de

doi:10.1016/j.neuron.2018.06.026

Cited by 61 publications

(53 citation statements)

References 65 publications

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“…The study characterizing Slitrk3 KO mice has further supported selective involvement of Slitrk3 in inhibitory synapse development (Takahashi et al, 2012 ) by detecting a decrease in inhibitory synapse number and function as well as seizure behaviors. On the other hand, RNAi-based knockdown studies as well as neuronal overexpression ones have indicated selective involvement of Slitrk1/2 in excitatory synapse number and function (Yim et al, 2013 ; Schroeder et al, 2018 ; Han et al, 2019 ). Also, Slitrk1 KO mice exhibit elevated anxiety behaviors (Katayama et al, 2010 ), and Slitrk5 KO mice display obsessive-compulsive–like behaviors with decreases in glutamate receptors and excitatory synaptic transmission in cortico-striatum synapses (Shmelkov et al, 2010 ).…”

Section: Lar-rptp-based Synaptic Organizing Complexesmentioning

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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Section: Lar-rptp-based Synaptic Organizing Complexesmentioning

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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“…Extracellular interactions of PTPσ with postsynaptic ligands could control the function of VGCCs (Muller et al, 2010). This hypothesis was supported by a study showing that KD of Slitrk1, a postsynaptic ligand for PTPσ, increased the number of docked SVs, 28 mimicking some of the loss-of-function phenotype of PTPσ cKO (Schroeder et al, 2018) (Fig 3).…”

Section: Ptpσ Requires Various Molecular Mechanisms To Regulate Excitmentioning

confidence: 68%

Presynaptic PTPσ organizes neurotransmitter release machinery at excitatory synapses

Han

Lee

Lim

et al. 2020

Preprint

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Leukocyte common antigen-related receptor tyrosine phosphatases (LAR-RPTPs) are evolutionarily conserved presynaptic organizers. The synaptic role of vertebrate LAR-RPTPs in vivo, however, remains unclear. This study systematically analyzed the effects of genetic deletions of LAR-RPTP genes by generating single conditional knockout (cKO) mice targeting PTPσ and PTPδ. Although the numbers of synapses were reduced in cultured neurons deficient in individual PTPs, abnormalities in synaptic transmission, synaptic ultrastructures, and vesicle localization were observed only in PTPσ-deficient neurons. Strikingly, loss of presynaptic PTPσ reduced neurotransmitter release prominently at excitatory synapses, concomitant with drastic reductions in excitatory innervations onto postsynaptic target areas in vivo. However, postsynaptic PTPσ deletion had no effect on excitatory synaptic strength. Furthermore, conditional deletion of PTPσ in ventral CA1 specifically altered anxiety-like behaviors. Taken together, these results demonstrate that PTPσ is a bona fide presynaptic adhesion molecule that controls neurotransmitter release and excitatory inputs.11 100 nm from the presynaptic AZ membrane, was significantly increased in PTPσ-deficient presynaptic terminals (Fig 2E). In contrast, the number of tethered vesicles, defined as vesicular structures docked at presynaptic AZ membranes, was only marginally increased, an increase that was not statistically significant (Fig 2F). Surprisingly, the AZ length was increased by ~30% (Fig 2A and 2B), similar to the doubled AZ size in Caenorhabditis elegans mutants lacking ptp-3A, an orthologue of the type IIa RPTP gene (Ackley et al, 2005, Han et al, 2019. Consistent with this, a corresponding increase (~15%) in PSD length was observed (Fig 2A and 2C). This phenotype was not observed in PTPδ-deficient presynaptic terminals, nor were there any alterations in other anatomical parameters (Fig 2H-2M). Quantitative immunoblot analysis of PTPσand PTPδ-deficient neurons showed comparable expression of presynaptic AZ and PSD proteins, although the level of RIM1/2 was significantly lower in PTPδ-deficient neurons (Fig 2G, 2N, Appendix Fig 3A and 3B). These results suggest that PTPσ and PTPδ are not functionally redundant, and that PTPσ, but not PTPδ, is crucial in controlling the structural organization of both presynaptic AZs and PSDs.

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“…Although the current study focused on neuronal impairments, non-neuronal populations were also strongly affected by heroin and potentially contribute to addiction pathology. For example, SLITRK1, the most significantly altered gene in the non-neuronal population, is closely linked to synaptic plasticity 60 .…”

Section: Discussionmentioning

confidence: 99%

Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder

et al. 2020

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The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.

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A Modular Organization of LRR Protein-Mediated Synaptic Adhesion Defines Synapse Identity

Cited by 61 publications

References 65 publications

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

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

Presynaptic PTPσ organizes neurotransmitter release machinery at excitatory synapses

Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder

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