The Potential Role of AMPA Receptor Trafficking in Autism and Other Neurodevelopmental Conditions

Niescier, Robert F.; Lin, Yu‐Chih

doi:10.1016/j.neuroscience.2021.09.013

Cited by 17 publications

(7 citation statements)

References 164 publications

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“…AMPARs, as the primary mediator for excitatory synaptic transmission, have been previously reported to be dysregulated at various levels in ASD, including altered gene expression, alternative splicing, RNA modification, receptor trafficking, and subunit composition (Li et al, 2016a ; Achuta et al, 2018 ; Yennawar et al, 2019 ; Niescier and Lin, 2021 ; Tramarin et al, 2018 ). Our study reveals a novel mechanism in AMPAR dysregulation in UBE3A-dependent ASD, i.e., defective nuclear-cytosol trafficking of AMPAR mRNA leading to a suppression in AMPAR synthesis and synaptic accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in various ASD-related genes, such as FMRP in Fragile X syndrome and MECP2 in Rett syndrome, have been linked to AMPAR trafficking defects (Nakamoto et al, 2007 ; Li et al, 2016b ). Similarly, other autism candidate genes including NLGNs, IQSEC2, DOCK4 , and STXBP5 , are also implicated in AMPAR trafficking (Niescier and Lin, 2021 ). Altered AMPAR subunit composition, which can be induced by several ASD genes such as SHANK2 and SHANK3 , could impair synaptic maturation and circuit formation (Ha et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

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mRNA nuclear retention reduces AMPAR expression and promotes autistic behavior in UBE3A-overexpressing mice

Tian,

Yu,

Yun

et al. 2024

EMBO Rep

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UBE3A is a common genetic factor in ASD etiology, and transgenic mice overexpressing UBE3A exhibit typical autistic-like behaviors. Because AMPA receptors (AMPARs) mediate most of the excitatory synaptic transmission in the brain, and synaptic dysregulation is considered one of the primary cellular mechanisms in ASD pathology, we investigate here the involvement of AMPARs in UBE3A-dependent ASD. We show that expression of the AMPAR GluA1 subunit is decreased in UBE3A-overexpressing mice, and that AMPAR-mediated neuronal activity is reduced. GluA1 mRNA is trapped in the nucleus of UBE3A-overexpressing neurons, suppressing GluA1 protein synthesis. Also, SARNP, an mRNA nuclear export protein, is downregulated in UBE3A-overexpressing neurons, causing GluA1 mRNA nuclear retention. Restoring SARNP levels not only rescues GluA1 mRNA localization and protein expression, but also normalizes neuronal activity and autistic behaviors in mice overexpressing UBE3A. These findings indicate that SARNP plays a crucial role in the cellular and behavioral phenotypes of UBE3A-induced ASD by regulating nuclear mRNA trafficking and protein translation of a key AMPAR subunit.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mRNA nuclear retention reduces AMPAR expression and promotes autistic behavior in UBE3A-overexpressing mice

Tian,

Yu,

Yun

et al. 2024

EMBO Rep

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“…In particular, due to changes in ASD risk genes, a series of presynaptic and postsynaptic proteins may be affected [ 17 ]. In recent years, in-depth research on the molecular basis and characteristics of ASD has revealed the potential role of AMPA receptor trafficking in ASD [ 18 ]. The AMPA receptor is composed of GluA1-4 subunits, in which GluA1/GluA2 heterotetramers are the most frequent combination in the forebrain [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Novel GRIA2 variant in a patient with atypical autism spectrum disorder and psychiatric symptoms: a case report

et al. 2022

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Background As sequencing technology has advanced in recent years, a series of synapse-related gene variants have been reported to be associated with autism spectrum disorders (ASDs). The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor is a subtype of the ionotropic glutamate receptor, whose number or composition changes can regulate the strength and plasticity of synapses. Case presentation Here, we report a de novo GRIA2 variant (NM_001083619.3: c.2308G > A, p.Ala770Thr) in a patient with obvious behavior regression and psychiatric symptoms. It encodes GluA2, which is the crucial subunit of the AMPA receptor, and the missense variation is predicted to result in instability of the protein structure. Conclusions The association between GRIA2 variants and onset of ASD symptoms is rare, and our study expands the spectrum of phenotypic variations. For patients with an unexplained etiology of ASD accompanied by psychiatric symptoms, genetic causes should be considered, and a complete genetic evaluation should be performed.

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“…The above discussion alludes to how AMPA receptors may influence circuit level processes in autism pathogenesis, but the majority of work on AMPA receptor dysfunction in autism has focused on how AMPA receptor perturbations are associated with autism on the molecular level ( 50 ). To this end, we will discuss how neuronal activity, AMPA receptor signaling, and the dynamic composition of the post-synaptic density (PSD) combine to play a key role in typical neurodevelopment and may be a key site for the pathogenesis of autism.…”

Section: The Association Of Ampa Receptor With Cerebro-cerebellar Cir...mentioning

confidence: 99%

Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction

Jimenez-Gomez,

Nguyen,

Gill

2024

Front. Psychiatry

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Autism spectrum disorders represent a diverse etiological spectrum that converge on a syndrome characterized by discrepant deficits in developmental domains often highlighted by concerns in socialization, sensory integration, and autonomic functioning. Importantly, the incidence and prevalence of autism spectrum disorders have seen sharp increases since the syndrome was first described in the 1940s. The wide etiological spectrum and rising number of individuals being diagnosed with the condition lend urgency to capturing a more nuanced understanding of the pathogenic mechanisms underlying the autism spectrum disorders. The current review seeks to understand how the disruption of AMPA receptor (AMPAr)-mediated neurotransmission in the cerebro-cerebellar circuit, particularly in genetic autism related to SHANK3 or SYNGAP1 protein dysfunction function and autism associated with in utero exposure to the anti-seizure medications valproic acid and topiramate, may contribute to the disease presentation. Initially, a discussion contextualizing AMPAr signaling in the cerebro-cerebellar circuitry and microstructural circuit considerations is offered. Subsequently, a detailed review of the literature implicating mutations or deletions of SHANK3 and SYNGAP1 in disrupted AMPAr signaling reveals how bidirectional pathogenic modulation of this key circuit may contribute to autism. Finally, how pharmacological exposure may interact with this pathway, via increased risk of autism diagnosis with valproic acid and topiramate exposure and potential treatment of autism using AMPAr modulator perampanel, is discussed. Through the lens of the review, we will offer speculation on how neuromodulation may be used as a rational adjunct to therapy. Together, the present review seeks to synthesize the disparate considerations of circuit understanding, genetic etiology, and pharmacological modulation to understand the mechanistic interaction of this important and complex disorder.

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The Potential Role of AMPA Receptor Trafficking in Autism and Other Neurodevelopmental Conditions

Cited by 17 publications

References 164 publications

mRNA nuclear retention reduces AMPAR expression and promotes autistic behavior in UBE3A-overexpressing mice

mRNA nuclear retention reduces AMPAR expression and promotes autistic behavior in UBE3A-overexpressing mice

Novel GRIA2 variant in a patient with atypical autism spectrum disorder and psychiatric symptoms: a case report

Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction

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