Restoring glutamate receptosome dynamics at synapses rescues autism-like deficits in Shank3-deficient mice

Moutin, Enora; Sakkaki, Sophie; Compan, Vincent; Bouquier, Nathalie; Giona, Federica; Areias, Julie; Goyet, Elise; Hemonnot-Girard, Anne-Laure; Seube, Vincent; Glasson, Bastien; Bénac, Nathan; Chastagnier, Yan; Raynaud, Fabrice; Audinat, Etienne; Groc, Laurent; Maurice, Tangui; Sala, Carlo; Verpelli, Chiara; Perroy, Julie

doi:10.1038/s41380-021-01230-x

Cited by 25 publications

(22 citation statements)

References 58 publications

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“…In neurons, SHANK3 links glutamate receptors, NMDARs and AMPARs, to the actin skeleton. This link is established by the interaction of SHANK3 with multiple postsynaptic density proteins and a loss of SHANK3 leads to reduced levels of these PSD proteins including Homer1b/c, PSD95, GKAP, NMDARs, and AMPARs, which together form the so-called glutamate receptosome [ 33 , 40 , 61 , 89 , 90 ]. These are proteins that neurexins also interact with indirectly via PDZ interactions and are important for cytoskeleton regulation, synaptic transmission, and plasticity [ 44 , 56 ].…”

Section: From Neural Circuit To Targeted Gene-based Therapymentioning

confidence: 99%

“…Specifically, in the striatum and cortex SHANK3 performs an essential function in glutamate receptor signaling by recruiting Homer1b/c to the PSD [ 62 ]. The deficits in synaptic transmission and plasticity caused by a loss of Shank3 include reduced glutamatergic transmission, deficient long-term potentiation (LTP), impairments in mTOR activation, and altered NMDA/AMPA ratios in the prefrontal cortex, cerebellum, and hippocampus [ 40 , 61 , 63 , 64 , 90 ]. Furthermore, Shank3 deletions also lead to changes in spine morphology and density in striatal and hippocampal neurons.…”

Section: From Neural Circuit To Targeted Gene-based Therapymentioning

confidence: 99%

“…Another potential downstream drug candidate for ASD is the PSD95–GKAP–Shank–Homer complex or ‘glutamate receptosome’. Remodeling of the glutamate receptosome is necessary for the induction of NMDA-dependent plasticity and is required for neuronal plasticity via the activation of mTOR signaling pathways [ 90 ]. This glutamate receptosome is interrupted by the Shank3 mutation in mice, leading to altered plasticity and ASD-like behaviors such as stereotyped behaviors.…”

Section: From Asd Development To Windows Of Treatment Opportunitymentioning

confidence: 99%

“…This glutamate receptosome is interrupted by the Shank3 mutation in mice, leading to altered plasticity and ASD-like behaviors such as stereotyped behaviors. Early restoration of this complex between PND 6-8 restored the ASD-like deficits in Shank3 knockout mice [ 90 ]. Moreover, pharmacological enhancement of specifically metabotropic glutamate receptor 5 (mGlu5) signaling also reverses the behavioral deficits in Shank3 knockout mice [ 62 ].…”

Section: From Asd Development To Windows Of Treatment Opportunitymentioning

confidence: 99%

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Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

Riemersma

Havekes

Kas

2021

Genes

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Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by differences in social interaction, repetitive behaviors, restricted interests, and sensory differences beginning early in life. Especially sensory symptoms are highly correlated with the severity of other behavioral differences. ASD is a highly heterogeneous condition on multiple levels, including clinical presentation, genetics, and developmental trajectories. Over a thousand genes have been implicated in ASD. This has facilitated the generation of more than two hundred genetic mouse models that are contributing to understanding the biological underpinnings of ASD. Since the first symptoms already arise during early life, it is especially important to identify both spatial and temporal gene functions in relation to the ASD phenotype. To further decompose the heterogeneity, ASD-related genes can be divided into different subgroups based on common functions, such as genes involved in synaptic function. Furthermore, finding common biological processes that are modulated by this subgroup of genes is essential for possible patient stratification and the development of personalized early treatments. Here, we review the current knowledge on behavioral rodent models of synaptic dysfunction by focusing on behavioral phenotypes, spatial and temporal gene function, and molecular targets that could lead to new targeted gene-based therapy.

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Section: From Neural Circuit To Targeted Gene-based Therapymentioning

confidence: 99%

Section: From Neural Circuit To Targeted Gene-based Therapymentioning

confidence: 99%

Section: From Asd Development To Windows Of Treatment Opportunitymentioning

confidence: 99%

Section: From Asd Development To Windows Of Treatment Opportunitymentioning

confidence: 99%

See 2 more Smart Citations

Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

Riemersma

Havekes

Kas

2021

Genes

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“…Shank3 is part of the glutamate receptor body, which physically connects the parent-NMDA receptor to the metabolite mGlu5 receptor by interacting with the scaffold-folding protein PSD95-GKAP-Shank3-Homer [ 105 ]. These findings may suggest an important role of IGF-1 on correcting the integrity of the glutamate receptosome required for the synaptic transmission and plasticity.…”

Section: Igf-1 Modulation Of Glutamate-induced Synaptic Plasticitymentioning

confidence: 99%

Research Progress on Neuroprotection of Insulin-like Growth Factor-1 towards Glutamate-Induced Neurotoxicity

Liu

Rubin

et al. 2022

Cells

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Insulin-like growth factor-1 (IGF-1) and its binding proteins and receptors are widely expressed in the central nervous system (CNS), proposing IGF-1-induced neurotrophic actions in normal growth, development, and maintenance. However, while there is convincing evidence that the IGF-1 system has specific endocrine roles in the CNS, the concept is emerging that IGF-I might be also important in disorders such as ischemic stroke, brain trauma, Alzheimer’s disease, epilepsy, etc., by inducing neuroprotective effects towards glutamate-mediated excitotoxic signaling pathways. Research in rodent models has demonstrated rescue of pathophysiological and behavioral abnormalities when IGF-1 was administered by different routes, and several clinical studies have shown safety and promise of efficacy in neurological disorders of the CNS. Focusing on the relationship between IGF-1-induced neuroprotection and glutamate-induced excitatory neurotoxicity, this review addresses the research progress in the field, intending to provide a rationale for using IGF-I clinically to confer neuroprotective therapy towards neurological diseases with glutamate excitotoxicity as a common pathological pathway.

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From synaptic dysfunction to atypical emotional processing in autism

Reis,

Monteiro

2024

FEBS Letters

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Autism spectrum disorder (ASD) is a complex neurodevelopmental condition mainly characterized by social impairments and repetitive behaviors. Among these core symptoms, a notable aspect of ASD is the presence of emotional complexities, including high rates of anxiety disorders. The inherent heterogeneity of ASD poses a unique challenge in understanding its etiological origins, yet the utilization of diverse animal models replicating ASD traits has enabled researchers to dissect the intricate relationship between autism and atypical emotional processing. In this review, we delve into the general findings about the neural circuits underpinning one of the most extensively researched and evolutionarily conserved emotional states: fear and anxiety. Additionally, we explore how distinct ASD animal models exhibit various anxiety phenotypes, making them a crucial tool for dissecting ASD's multifaceted nature. Overall, to a proper display of fear response, it is crucial to properly process and integrate sensorial and visceral cues to the fear‐induced stimuli. ASD individuals exhibit altered sensory processing, possibly contributing to the emergence of atypical phobias, a prevailing anxiety disorder manifested in this population. Moreover, these individuals display distinctive alterations in a pivotal fear and anxiety processing hub, the amygdala. By examining the neurobiological mechanisms underlying fear and anxiety regulation, we can gain insights into the factors contributing to the distinctive emotional profile observed in individuals with ASD. Such insights hold the potential to pave the way for more targeted interventions and therapies that address the emotional challenges faced by individuals within the autism spectrum.

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Restoring glutamate receptosome dynamics at synapses rescues autism-like deficits in Shank3-deficient mice

Abstract: HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

Cited by 25 publications

References 58 publications

Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

Research Progress on Neuroprotection of Insulin-like Growth Factor-1 towards Glutamate-Induced Neurotoxicity

From synaptic dysfunction to atypical emotional processing in autism

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