Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development

Li, Jun; Han, Wenyan; Pelkey, Kenneth A.; Duan, Jingjing; Mao, Xiao‐Ming; Wang, Yaxian; Craig, Michael T.; Dong, Lijin; Petralia, Ronald S.; McBain, Chris J.; Lü, Wei

doi:10.1016/j.neuron.2017.10.003

Cited by 74 publications

(82 citation statements)

References 62 publications

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“…Alterations of GABAergic neurotransmission in thalamocortical circuits are also likely to contribute to modifications of EEG activity during wakefulness, NREM and REM sleep in Nlgn2 −/− mice. The general increase in absolute spectral activity, especially for frequencies overlapping alpha, sigma and beta activity bands (i.e., 9 to 22 Hz) could originate from a global deficit in inhibition as pointed out by decreased mIPSCs and increased excitability reported under Nlgn2 downregulation [ 16 , 17 ], and by the role of NLGN2 in the development of GABAergic synapses [ 43 ]. In parallel, our observation of high delta activity in Nlgn2 −/− mice is consistent with findings of decreased spectral power in the delta range under administration of GABA A receptor agonists [ 21 , 22 , 44 ], given the regulation of the clustering of GABA A receptors by NLGN2 [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

The effect of Neuroligin-2 absence on sleep architecture and electroencephalographic activity in mice

et al. 2018

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Sleep disorders are comorbid with most psychiatric disorders, but the link between these is not well understood. Neuroligin-2 (NLGN2) is a cell adhesion molecule that plays roles in synapse formation and neurotransmission. Moreover, NLGN2 has been associated with psychiatric disorders, but its implication in sleep remains underexplored. In the present study, the effect of Nlgn2 knockout (Nlgn2−/−) on sleep architecture and electroencephalographic (EEG) activity in mice has been investigated. The EEG and electromyogram (EMG) were recorded in Nlgn2−/− mice and littermates for 24 h from which three vigilance states (i.e., wakefulness, rapid eye movement [REM] sleep, non-REM [NREM] sleep) were visually identified. Spectral analysis of the EEG was performed for the three states. Nlgn2−/− mice showed more wakefulness and less NREM and REM sleep compared to wild-type (Nlgn2+/+) mice, especially during the dark period. This was accompanied by changes in the number and duration of individual episodes of wakefulness and sleep, indexing changes in state consolidation, as well as widespread changes in EEG spectral activity in all states. Abnormal ‘hypersynchronized’ EEG events have also been observed predominantly in Nlgn2−/− mice. These events were mainly observed during wakefulness and REM sleep. In addition, Nlgn2−/− mice showed alterations in the daily time course of NREM sleep delta (1–4 Hz) activity, pointing to modifications in the dynamics of sleep homeostasis. These data suggest that NLGN2 participates in the regulation of sleep duration as well as EEG activity during wakefulness and sleep.

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Section: Discussionmentioning

confidence: 99%

The effect of Neuroligin-2 absence on sleep architecture and electroencephalographic activity in mice

et al. 2018

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“…However, Aβ also diminishes GABAergic inhibitory synaptic transmission by enhancing GABA A receptor endocytosis (Ulrich, 2015 ). Given that some synaptic organizers such as NLGN2 and Slitrk3 preferentially regulate inhibitory synapse organization (Poulopoulos et al, 2009 ; Takahashi et al, 2012 ; Li et al, 2017 ), further studies would be also necessary to address whether and how synaptic organizers are involved in Aβ-induced dysfunction of inhibitory synapses and dysregulation of GABA A receptors.…”

Section: Discussionmentioning

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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“…Mouse hippocampal cultured neurons were transfected with indicated FRRS1L sgRNA #1 or sgRNA #3 plasmids by calcium phosphate transfection at DIV2 as described ( Li et al, 2017 ). Endogenous GluA1 in live neurons was labeled with a mouse monoclonal antibody against an extracellular epitope of GluA1 (clone RH95; 5 μg/ml) in conditioned culture medium for 15 min at 37°C at DIV16.…”

Section: Methodsmentioning

confidence: 99%

Ferric Chelate Reductase 1 Like Protein (FRRS1L) Associates with Dynein Vesicles and Regulates Glutamatergic Synaptic Transmission

Han

Wang

et al. 2017

Front. Mol. Neurosci.

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In the brain, AMPA receptors (AMPARs)-mediated excitatory synaptic transmission is critically regulated by the receptor auxiliary subunits. Recent proteomic studies have identified that Ferric Chelate Reductase 1 Like protein (FRRS1L), whose mutations in human lead to epilepsy, choreoathetosis, and cognitive deficits, is present in native AMPAR complexes in the brain. Here we have characterized FRRS1L in both heterologous cells and in mouse neurons. We found that FRRS1L interacts with both GluA1 and GluA2 subunits of AMPARs, but does not form dimers/oligomers, in HEK cells. In mouse hippocampal neurons, recombinant FRRS1L at the neuronal surface partially co-localizes with GluA1 and primarily localizes at non-synaptic membranes. In addition, native FRRS1L in hippocampus is localized at dynein, but not kinesin5B, vesicles. Functionally, over-expression of FRRS1L in hippocampal neurons does not change glutamatergic synaptic transmission. In contrast, single-cell knockout (KO) of FRRS1L strongly reduces the expression levels of the GluA1 subunit at the neuronal surface, and significantly decreases AMPAR-mediated synaptic transmission in mouse hippocampal pyramidal neurons. Taken together, these data characterize FRRS1L in heterologous cells and neurons, and reveal an important role of FRRS1L in the regulation of excitatory synaptic strength.

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Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development

Cited by 74 publications

References 62 publications

The effect of Neuroligin-2 absence on sleep architecture and electroencephalographic activity in mice

The effect of Neuroligin-2 absence on sleep architecture and electroencephalographic activity in mice

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

Ferric Chelate Reductase 1 Like Protein (FRRS1L) Associates with Dynein Vesicles and Regulates Glutamatergic Synaptic Transmission

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