Disruption of the autism-associated gene <i>SCN2A</i> alters synaptic development and neuronal signaling in patient iPSC-glutamatergic neurons

Brown, Chad O; Uy, Jarryll; Murtaza, Nadeem; Rosa, Elyse; Alfonso, Alexandria; Xing, Sansi; Dave, Biren M.; Kilpatrick, Savannah; Cheng, Annie A.; White, Stuart C.; Howe, Jennifer; Scherer, Stephen W.; Lu, Yu; Singh, Karun K.

doi:10.1101/2021.09.14.460368

Cited by 2 publications

(1 citation statement)

References 93 publications

(150 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have reported similar hyperexcitable neurons that carry ASD-and epilepsy-related mutations for SCN2A (Sodium channel protein type 2 subunit alpha) (67,68). Both epilepsy and ASD are also reported in patients with PRICKLE2 mutations (26,27), while Prickle2 knockout mice display a lower threshold for seizures (26) and ASD-like behaviors (27).…”

Section: Prickle2 Function In Asd and Epilepsymentioning

confidence: 97%

The core PCP protein Prickle2 regulates axon number and AIS maturation by binding to AnkG and modulating microtubule bundling

et al. 2022

View full text Add to dashboard Cite

Core planar cell polarity (PCP) genes, which are involved in various neurodevelopmental disorders such as neural tube closure, epilepsy, and autism spectrum disorder, have poorly defined molecular signatures in neurons, mostly synapse-centric. Here, we show that the core PCP protein Prickle-like protein 2 (Prickle2) controls neuronal polarity and is a previously unidentified member of the axonal initial segment (AIS) proteome. We found that Prickle2 is present and colocalizes with AnkG480, the AIS master organizer, in the earliest stages of axonal specification and AIS formation. Furthermore, by binding to and regulating AnkG480, Prickle2 modulates its ability to bundle microtubules, a crucial mechanism for establishing neuronal polarity and AIS formation. Prickle2 depletion alters cytoskeleton organization, and Prickle2 levels determine both axon number and AIS maturation. Last, early Prickle2 depletion produces impaired action potential firing.

show abstract

Section: Prickle2 Function In Asd and Epilepsymentioning

confidence: 97%

The core PCP protein Prickle2 regulates axon number and AIS maturation by binding to AnkG and modulating microtubule bundling

et al. 2022

View full text Add to dashboard Cite

show abstract

Paradoxical Hyperexcitability in Disorders of Neurodevelopment

Antoine

2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Autism Spectrum Disorder (ASD), Rett syndrome (RTT) and Angelman Syndrome (AS) are neurodevelopmental disorders (NDDs) that share several clinical characteristics, including displays of repetitive movements, developmental delays, language deficits, intellectual disability, and increased susceptibility to epilepsy. While several reviews address the biological basis of non-seizure-related ASD phenotypes, here, I highlight some shared biological mechanisms that may contribute to increased seizure susceptibility. I focus on genetic studies identifying the anatomical origin of the seizure phenotype in loss-of-function, monogenic, mouse models of these NDDs, combined with insights gained from complementary studies quantifying levels of synaptic excitation and inhibition. Epilepsy is characterized by a sudden, abnormal increase in synchronous activity within neuronal networks, that is posited to arise from excess excitation, largely driven by reduced synaptic inhibition. Primarily for this reason, elevated network excitability is proposed to underlie the causal basis for the ASD, RTT, and AS phenotypes. Although, mouse models of these disorders replicate aspects of the human condition, i.e., hyperexcitability discharges or seizures on cortical electroencephalograms, measures at the synaptic level often reveal deficits in excitatory synaptic transmission, rather than too much excitation. Resolving this apparent paradox has direct implications regarding expected outcomes of manipulating GABAergic tone. In particular, in NDDs associated with seizures, cortical circuits can display reduced, rather than normal or increased levels of synaptic excitation, and therefore suggested treatments aimed at increasing inhibition could further promote hypoactivity instead of normality. In this review, I highlight shared mechanisms across animal models for ASD, RTT, and AS with reduced synaptic excitation that nevertheless promote hyperexcitability in cortical circuits.

show abstract

Disruption of the autism-associated gene SCN2A alters synaptic development and neuronal signaling in patient iPSC-glutamatergic neurons

Cited by 2 publications

References 93 publications

The core PCP protein Prickle2 regulates axon number and AIS maturation by binding to AnkG and modulating microtubule bundling

The core PCP protein Prickle2 regulates axon number and AIS maturation by binding to AnkG and modulating microtubule bundling

Paradoxical Hyperexcitability in Disorders of Neurodevelopment

Contact Info

Product

Resources

About