Regulation of hippocampal long term depression by Neuroligin 1

Dang, Rui; Qi, Junxia; Liu, An; Ren, Qiaoyun; Lv, Dandan; Han, Lifang; Zhou, Zikai; Cao, Fan; Xie, Wei; Jia, Zhengping

doi:10.1016/j.neuropharm.2018.09.035

Cited by 19 publications

(19 citation statements)

References 59 publications

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“…Indeed, 3xTg-AD females have repeatedly been reported to have, in particular, higher hAPP and Aβ levels than males 60,62,63 . Alternatively, a compensatory mechanism linked to the encoding of other NLGNs by sex chromosomes 64,65 , could also contribute to the sex-dependent decrease in NLGN1. Of interest is also that we found a genotype-independent decrease in NLGN1 level with age in male mice (also significant when females and males are pooled).…”

Section: Discussionmentioning

confidence: 99%

“…From these data, we cannot exclude a direct effect of neuronal death on NLGN1 level because the NLGN1 decrease paralleled the neuronal viability decrease. Still, these findings are revealing a synaptic component linked to the established neurotoxicity of Aβo as well as their correlation with cognitive functioning in AD patients and animal models [9][10][11][12][13][14][15][16][17][18] , given the roles of NLGN1 in cognition and its cellular correlates 3,[31][32][33]64 . Of note is that Aβ 1-40 fibrils, which are generally considered less neurotoxic than Aβo 11,19 , have also been shown to negatively impact NLGN1 protein level in the rat hippocampus 36 .…”

Section: Discussionmentioning

confidence: 99%

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Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

Dufort-Gervais

Provost

Charbonneau

et al. 2020

Sci Rep

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Synapse loss occurs early and correlates with cognitive decline in Alzheimer's disease (AD). Synaptotoxicity is driven, at least in part, by amyloid-beta oligomers (Aβo), but the exact synaptic components targeted by Aβo remain to be identified. We here tested the hypotheses that the post-synaptic protein Neuroligin-1 (NLGN1) is affected early in the process of neurodegeneration in the hippocampus, and specifically by Aβo, and that it can modulate Aβo toxicity. We found that hippocampal NLGN1 was decreased in patients with AD in comparison to patients with mild cognitive impairment and control subjects. Female 3xTg-AD mice also showed a decreased NLGN1 level in the hippocampus at an early age (i.e., 4 months). We observed that chronic hippocampal Aβo injections initially increased the expression of one specific Nlgn1 transcript, which was followed by a clear decrease. Lastly, the absence of NLGN1 decreased neuronal counts in the dentate gyrus, which was not the case in wild-type animals, and worsens impairment in spatial learning following chronic hippocampal Aβo injections. Our findings support that NLGN1 is impacted early during neurodegenerative processes, and that Aβo contributes to this effect. Moreover, our results suggest that the presence of NLGN1 favors the cognitive prognosis during Aβo-driven neurodegeneration. Synapse loss is an early event in the pathogenesis of Alzheimer's disease (AD) and correlates with cognitive decline of the patients 1-3. Hippocampus-dependent memory for recent facts and events (explicit memory) is among the first type of memory that is affected in the disease because of the neurodegenerative process that rapidly and gradually takes place in the hippocampus at the onset of AD 4,5. More precisely, within the hippocampal network, the perforant path that connects the entorhinal cortex to the dentate gyrus (DG) is one of the earliest and most severely affected pathways in AD 6,7. This suggests that the DG is among sites showing initial signs of synaptic dysfunction, including in glutamatergic transmission 8 , and that it could represent an area of particular relevance for early interventions. Despite decades of research focused on the amyloid-beta (Aβ) peptide, its causal role in AD pathogenesis remains unclear at the molecular level. However, strong evidence suggests that soluble Aβ oligomers (Aβo) are particularly neurotoxic and that their presence can correlate with memory deficits in AD patients and animal models, especially when considering oligomers derived from Aβ 1-42 peptides 9-18. Soluble Aβo start to accumulate in the human brain ~10 to 15 years before clinical symptoms and were shown to induce losses of excitatory synapses and neurons 19-22. The oligomerization of Aβ is rapid and it has been suggested that Aβ toxicity results

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

Dufort-Gervais

Provost

Charbonneau

et al. 2020

Sci Rep

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“…Moreover, whereas Nlg1 KO was shown to affect primarily basal NMDAR-mediated synaptic transmission, we find instead strong effects of acute Nlg1 tyrosine phosphorylation on basal AMPAR-mediated EPSCs, and no alteration of NMDAR-dependent EPSCs. The fact that AMPAR-mediated EPSCs are not altered in the Nlg1 KO (Chanda et al, 2017) may result from the compensatory expression of scaffolding or adhesion molecules, in particular Nlg3 (Dang et al, 2018), which also interacts with PSD-95. This would explain the fact that a dual Nlg1/3 (and triple Nlg1/2/3) KO are required to alter AMPARs levels and AMPAR-mEPSCs in cultured neurons (Chanda et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to differences in experimental preparations, these studies relying on the manipulation of the Nlg expression level all have potential biases, including the compensatory expression of proteins in the case of KO (Dang et al, 2018), off-target effects of inhibitory RNAs (Alvarez et al, 2006), and mislocalization of overexpressed Nlgs, e.g. Nlg1 at inhibitory synapses and Nlg2 at excitatory synapses (Chih et al, 2006;Letellier et al, 2018;Nguyen et al, 2016;Tsetsenis et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation

Letellier

Lagardère

Tessier

et al. 2019

Preprint

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AbstractNeuroligins (Nlgs) are adhesion proteins mediating trans-synaptic contacts in neurons. However, conflicting results around their role in synaptic differentiation arise from the various techniques used to manipulate Nlg expression. Orthogonally to these approaches, we triggered here the phosphorylation of endogenous Nlg1 in CA1 hippocampal neurons using a photoactivatable tyrosine kinase receptor (optoFGFR1). Light stimulation for 24 h selectively increased dendritic spine density and AMPA receptor-mediated EPSCs in wild-type neurons, but not in Nlg1 knock-out neurons or when endogenous Nlg1 was replaced by a non-phosphorylatable mutant (Y782F). Moreover, light stimulation of optoFGFR1 partially occluded LTP. Combined with computer simulations, our data support a model by which Nlg1 tyrosine phosphorylation promotes the assembly of an excitatory post-synaptic scaffold that captures surface AMPA receptors. This optogenetic strategy thus highlights the impact of Nlg1 intracellular signaling in synaptic differentiation and potentiation, while enabling an acute control of these mechanisms.Impact StatementOrthogonal to the traditional paradigms used to manipulate neuroligin expression level, the optogenetic trigger of tyrosine phosphorylation supports a strong role of endogenous neuroligin-1 in excitatory synaptic differentiation and potentiation.

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“…neurexins 2 , neuroligins 3 , synaptic adhesion like molecules (SALMs) 4 , leucine-rich repeat (LRR) transmembrane neuronal proteins (LRRTMs) 5 , leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) 6 and netrin-G ligands (NGLs) 7 . The dysfunction of synaptic adhesion molecules have been proposed to be involved in onset and progression of various neurological disorders, which includes autism spectrum disorders, schizophrenia and Alzheimer's disease [8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPσ

Karki

Shkumatov

Bae

et al. 2020

Preprint

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Synaptic adhesion molecules play an important role in the formation, maintenance and refinement of neuronal connectivity. Recently, several leucine rich repeat (LRR) domain containing neuronal adhesion molecules have been characterized including netrin G-ligands, SLITRKs and the synaptic adhesion-like molecules (SALMs). Dysregulation of these adhesion molecules have been genetically and functionally linked to various neurological disorders. Here we investigated the molecular structure and mechanism of ligand interactions for the postsynaptic SALM3 adhesion protein with its presynaptic ligand, receptor protein tyrosine phosphatase σ (PTPσ). We solved the crystal structure of the dimerized leucine rich repeat (LRR) domain of SALM3, revealing the conserved structural features and mechanism of dimerization. Furthermore, we determined the complex structure of SALM3 with PTPσ using small angle X-ray scattering, revealing a 2:2 complex similar to that observed for SALM5. Solution studies unraveled additional flexibility for the complex structure, but validated the uniform mode of action for SALM3 and SALM5 to promote synapse formation. The relevance of the key interface residues was further confirmed by mutational analysis with cellular binding assays and artificial synapse formation assays.Collectively, our results suggest that SALM3 dimerization is a pre-requisite for the SALM3-PTPσ complex to exert synaptogenic activity.

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Regulation of hippocampal long term depression by Neuroligin 1

Cited by 19 publications

References 59 publications

Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation

Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPσ

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