GluA1-Shank3 interaction decreases in response to chronic neuronal depolarization

Ross, Madeline M.; Aizenman, Elias

doi:10.1016/j.neulet.2023.137305

Cited by 4 publications

(2 citation statements)

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“…Several mouse and rat models employing anti-SHANK3 antibodies at a hippocampal neuronal level have demonstrated structural dysregulation of NMDA and AMPA receptor clustering ( 99 ) and disrupted exocytosis of AMPA receptors via Rho-GAP interacting CIP4 homolog (Rich2) associations induced by, and later influencing of, LTP ( 100 ). Induced depolarization via potassium chloride of embryonic rat cortical neurons demonstrated that prolonged depolarization leads to increased glutamate effect via NMDA receptors in turn reducing SHANK3-GluA1 interactions and AMPA receptor function ( 101 ).…”

Section: Phelan Mcdermid Syndrome 22q13 Deletion and Other ...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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Section: Phelan Mcdermid Syndrome 22q13 Deletion and Other ...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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“…Otherwise, no cultures were excluded from the study. This primary cortical culture model was chosen as it is a well-validated model in our laboratory and we have previously demonstrated developmental increases in AMPAR and NMDAR subunit expression in these cultures consistent with their in vivo development (Ross & Aizenman, 2023;Sinor et al, 2000).…”

Section: Cerebrocortical Culturesmentioning

confidence: 99%

Copper induces neuron‐sparing, ferredoxin 1‐independent astrocyte toxicity mediated by oxidative stress

Gale,

Hartnett‐Scott,

Ross

et al. 2023

Journal of Neurochemistry

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Copper is an essential enzyme cofactor in oxidative metabolism, anti‐oxidant defenses, and neurotransmitter synthesis. However, intracellular copper, when improperly buffered, can also lead to cell death. Given the growing interest in the use of copper in the presence of the ionophore elesclomol (CuES) for the treatment of gliomas, we investigated the effect of this compound on the surround parenchyma—namely neurons and astrocytes in vitro. Here, we show that astrocytes were highly sensitive to CuES toxicity while neurons were surprisingly resistant, a vulnerability profile that is opposite of what has been described for zinc and other toxins. Bolstering these findings, a human astrocytic cell line was similarly sensitive to CuES. Modifications of cellular metabolic pathways implicated in cuproptosis, a form of copper‐regulated cell death, such as inhibition of mitochondrial respiration or knock‐down of ferredoxin 1 (FDX1), did not block CuES toxicity to astrocytes. CuES toxicity was also unaffected by inhibitors of apoptosis, necrosis or ferroptosis. However, we did detect the presence of lipid peroxidation products in CuES‐treated astrocytes, indicating that oxidative stress is a mediator of CuES‐induced glial toxicity. Indeed, treatment with anti‐oxidants mitigated CuES‐induced cell death in astrocytes indicating that oxidative stress is a mediator of CuES‐induced glial toxicity. Lastly, prior induction of metallothioneins 1 and 2 in astrocytes with zinc plus pyrithione was strikingly protective against CuES toxicity. As neurons express high levels of metallothioneins basally, these results may partially account for their resistance to CuES toxicity. These results demonstrate a unique toxic response to copper in glial cells which contrasts with the cell selectivity profile of zinc, another biologically relevant metal.image

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Cerebellar impairments in genetic models of autism spectrum disorders: A neurobiological perspective

Yenkoyan,

Grigoryan,

Kutna

et al. 2024

Progress in Neurobiology

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GluA1-Shank3 interaction decreases in response to chronic neuronal depolarization

Cited by 4 publications

References 50 publications

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

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

Copper induces neuron‐sparing, ferredoxin 1‐independent astrocyte toxicity mediated by oxidative stress

Cerebellar impairments in genetic models of autism spectrum disorders: A neurobiological perspective

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