Trans-Synaptic Signaling through the Glutamate Receptor Delta-1 Mediates Inhibitory Synapse Formation in Cortical Pyramidal Neurons

Fossati, Matteo; Assendorp, Nora; Gemin, Olivier; Colasse, Sabrina; Dingli, Florent; Arras, Guillaume; Loew, Damarys; Charrier, Cécile

doi:10.1016/j.neuron.2019.09.027

Cited by 80 publications

(74 citation statements)

References 117 publications

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“…Our connectome-transcriptome association analysis established a link between MDD-related changes in connectome gradients and gene expression enriched in transsynaptic signaling and calcium ion binding. Transsynaptic signaling is one of the most fundamental biological processes that contributes to a series of critical molecular functions, including instructing the formation of synapses, regulating synaptic plasticity, and matching pre- and postsynaptic neurons (60, 61). It enables the establishment of complex neuronal networks supporting effective information transfer and processing throughout the brain.…”

Section: Discussionmentioning

confidence: 99%

Connectome Gradient Dysfunction in Major Depression and Its Association with Gene Expression Profiles

Xia

Liu

Mechelli

et al. 2020

Preprint

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Major depressive disorder (MDD) is associated with coexisting disturbances in low-level sensory processing and high-order cognitive functions. However, the neurobiological mechanism underlying these phenotype deficits remains poorly understood. Here, we collect large-sample, multisite resting-state functional magnetic resonance imaging data (1,150 patients with MDD and 1,084 healthy controls) and postmortem gene expression data. We show downgraded and contracted connectome gradients that are mainly involved in primary sensory and transmodal regions in patients with MDD relative to healthy controls, leveraging an association with gene expression enriched in transsynaptic signaling and calcium ion binding. Machine learning approaches based on support vector regression suggest that the alterations of connectome gradients in patients significantly predict depressive symptoms. These results shed light on gradient dysfunction of the large-scale functional connectomes in MDD and consolidate the spectrum deficits of sensory and cognitive processing in this disorder.

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Section: Discussionmentioning

confidence: 99%

Connectome Gradient Dysfunction in Major Depression and Its Association with Gene Expression Profiles

Xia

Liu

Mechelli

et al. 2020

Preprint

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“…Numerous CAM variants exist due to large gene families and alternative splicing, generating a vast array of possible combinations of pre- and postsynaptic CAMs. Although some specific trans-synaptic interactions of CAMs have been reported to underlie distinct synaptic properties ( Chih et al, 2006 ; Fossati et al, 2019 ; Futai et al, 2013 ), elucidating synaptic CAM complexes that dictate synapse identity and function remains a major challenge.…”

Section: Introductionmentioning

confidence: 99%

Specific Neuroligin3–αNeurexin1 signaling regulates GABAergic synaptic function in mouse hippocampus

Uchigashima

Konno

Demchak

et al. 2020

eLife

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Synapse formation and regulation require signaling interactions between pre- and postsynaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the functions of neuroligins (Nlgns), postsynaptic CAMs, rely on the formation of trans-synaptic complexes with neurexins (Nrxns), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated via Nrxn interactions is unknown. Here we demonstrate that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3-expressing (VGT3+) inhibitory terminals and regulates VGT3+ inhibitory interneuron-mediated synaptic transmission in mouse organotypic slice cultures. Gene expression analysis of interneurons revealed that the αNrxn1+AS4 splice isoform is highly expressed in VGT3+ interneurons as compared with other interneurons. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrxn1+AS4 expressed in VGT3+ interneurons to regulate inhibitory synaptic transmission. Our results indicate that specific Nlgn–Nrxn signaling generates distinct functional properties at synapses.

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“…GluD1 is expressed in various brain regions in rodents, including the cerebral cortex, hippocampus, amygdala, bed nucleus of the stria terminalis, striatum, thalamus, nucleus accumbens, lateral habenular, and the dorsal raphe nucleus [3,32,33]. Similar to GluD2, postsynaptic GluD1 is required for synapse formation and maintenance in vitro via CBLN1/CBLN2/CBLN4 and presynaptic NRXN [7,9,[34][35][36][37]. In addition, GluD1 regulates group 1 mGluRs-mediated long-term depression in the hippocampus ex vivo [38].…”

Section: Introductionmentioning

confidence: 99%

GluD1 knockout mice with a pure C57BL/6N background show impaired fear memory, social interaction, and enhanced depressive-like behavior

et al. 2020

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The GluD1 gene is associated with susceptibility for schizophrenia, autism, depression, and bipolar disorder. However, the function of GluD1 and how it is involved in these conditions remain elusive. In this study, we generated a Grid1 gene-knockout (GluD1-KO) mouse line with a pure C57BL/6N genetic background and performed several behavioral analyses. Compared to a control group, GluD1-KO mice showed no significant anxiety-related behavioral differences, evaluated using behavior in an open field, elevated plus maze, a light-dark transition test, the resident-intruder test of aggression and sensorimotor gating evaluated by the prepulse inhibition test. However, GluD1-KO mice showed (1) higher locomotor activity in the open field, (2) decreased sociability and social novelty preference in the three-chambered social interaction test, (3) impaired memory in contextual, but not cued fear conditioning tests, and (4) enhanced depressive-like behavior in a forced swim test. Pharmacological studies revealed that enhanced depressive-like behavior in GluD1-KO mice was restored by the serotonin reuptake inhibitors imipramine and fluoxetine, but not the norepinephrine transporter inhibitor desipramine. In addition, biochemical analysis revealed no significant difference in protein expression levels, such as other glutamate receptors in the synaptosome and postsynaptic densities prepared from the frontal cortex and the hippocampus. These results suggest that GluD1 plays critical roles in fear memory, sociability, and depressive-like behavior.

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Trans-Synaptic Signaling through the Glutamate Receptor Delta-1 Mediates Inhibitory Synapse Formation in Cortical Pyramidal Neurons

Cited by 80 publications

References 117 publications

Connectome Gradient Dysfunction in Major Depression and Its Association with Gene Expression Profiles

Connectome Gradient Dysfunction in Major Depression and Its Association with Gene Expression Profiles

Specific Neuroligin3–αNeurexin1 signaling regulates GABAergic synaptic function in mouse hippocampus

GluD1 knockout mice with a pure C57BL/6N background show impaired fear memory, social interaction, and enhanced depressive-like behavior

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